PHARMACOLOGY 

CLINICAL  AND  EXPERIMENTAL 


A  GROUNDWORK  OF  MEDICAL 
TREATMENT,  BEING  A  TEXT-BOOK 
FOR  STUDENTS  AND  PHYSICIANS 

BY 

DR.  HANS  H.  MEYER,  of  Vienna 

AND 

DR.  R.  GOTTLIEB,  of  Heidelberg 

PROFESSORS  OF  PHARMACOLOGY 

AUTHORIZED  TRANSLATION  INTO  ENGLISH  BY 
JOHN  TAYLOR  HALSEY,  M.D., 

PROFESSOR  OF  PHARMACOLOGY,  THERAPEUTICS,  AND  CLINICAL  MEDICINE,  TULANE  UNIVERSITY 

WITH  65  TEXT  ILLUSTRATIONS,  7  IN  COLOR 


PHILADELPHIA  &  LONDON 
J.  B.  LIPPINCOTT  COMPANY 


COPYRIGHT,   1914 
BY  J.    B.   LIPPINCOTT  COMPANY 


Second   printing,    September,    1914 
Third  printing,  August,   1915 
Fourth  printing,  March,  1916 


Electrotyped  and  Printed  by  J.  B.  Lippincott  Company 
The  Washington  Square  Press,  Philadelphia,  U.  S.  A. 


AUTHORS'  PREFACE 

EXPERIMENTAL  pharmacology  in  its  widest  significance  deals  with 
the  reaction  of  living  organisms  to  various  chemical  agents  or,  otherwise 
expressed,  with  their  behavior  under  chemically  altered  conditions  of 
life.  Consequently  pharmacology  is  to  be  looked  upon  simply  as  one 
portion  of  biology. 

Among  the  endless  number  of  possible  pharmacological  reactions, 
those  possess  a  special  interest,  the  study  of  which  should  aid  the 
physician  in  practicing  his  healing  art.  This  portion  of  pharmacology, 
"scientific  drug  therapy"  in  a  more  restricted  sense,  forms  the  theo- 
retical basis  of  drug  treatment.  If  it  is  to  serve  its  full  usefulness 
in  explaining  the  ways  and  means  by  which  pathological  conditions 
may  be  influenced  by  drugs,  it  must  constantly  keep  in  closest  relations 
with  general  pathology,  i.e.,  the  study  of  the  various  disturbances  which 
occur  in  disease.  These  two  sciences  working  together  must  endeavor 
to  explain  how  pathologically  disturbed  functions  of  the  different 
organs  may  be  influenced  by  drugs  and  be  brought  back  to  the  norm. 
Here  lies  their  significance  for  clinical  teaching  and  medical  practice. 

Scientific  drug  therapy,  as  presented  by  us,  consequently  is  dealt 
with,  in  so  far  as  possible,  in  connection  with  the  physician's  point  of 
view  as  to  the  seat  and  cause  of  pathological  conditions.  For  this 
reason  we  have  divided  the  drugs  into  two  classes,  organotropic  (those 
influencing  organs  or  their  functions),  and  etiotropic  (those  acting  on 
the  causative  agents  of  disease),  and  have  thought  it  best  to  describe 
and  analyze  the  organotropic  pharmacological  actions  separately  for 
each  organ  or  functional  system. 

It  appears  to  us  not  at  all  disadvantageous  that  this  method  of 
presentation  requires  that  we  frequently  must  hark  back  to  a  considera- 
tion of  physiological  basic  principles,  for  in  view  of  the  fact  that  physi- 
ology has  been  displaced  from  among  the  final  subjects  in  the  examina- 
tions for  license,  it  becomes  more  important  than  ever  that  experimental 
pharmacology  should  refresh  and  keep  alive  the  knowledge  of  physi- 
ology in  the  consciousness  of  the  candidate  for  license. 

On  the  other  hand,  this  necessitates  the  omission  from  this  work  of 
all  notice  of  a  number  of  pharmacological  facts,  which,  while  they 

Hi 

369481 


iv  AUTHORS'  PREFACE 

possess  value  for  the  science  of  pharmacology,  do  not  appear  at  present 
to  be  available  as  material  for  building  the  foundation  of  a  scientific 
therapy. 

While  the  different  chapters,  as  shown  in  the  table  of  contents,  have 
been  written  by  one  or  the  other  of  us,  still  there  has  been  a  constant 
cooperation  and  collaboration  between  us,  which  leads  us  to  hope  that 
we  have  prepared  for  the  reader  a  homogeneous  work. 

H.  MEYER, 
R.  GOTTLIEB. 


TRANSLATOR'S  PREFACE 

IT  has  been  the  translator 's  aim  to  present  a  faithful  rendition  into 
English  of  the  original  work,  and  if  in  seeking  to  do  this  he  has  occa- 
sionally or  frequently  built  up  sentences  which  are  unwieldy  or  un- 
English,  he  hopes  that  this  will  be  borne  in  mind  as  extenuation  there- 
for. Occasionally,  where  he  has  thought  it  would  be  of  value,  he  has 
interpolated  comments  or  additions,  which  are  regularly  indicated  in 
the  text. 

J.  T.  H. 


CONTENTS 

CHAPTER  I 

PAGE 

PHARMACOLOGY  OF  THE  MOTOR  NERVE-ENDINGS  (Gottlieb) 1 

Depressants:  Curare — General  Discussions  of  Pharmacological  Actions — 
Stimulants. 

CHAPTER  II 

PHARMACOLOGY  OF  THE  CENTRAL  NERVOUS  SYSTEM  (Gottlieb) 11 

Excitants — Strychnine — General  Discussion  of  Alkaloids — Convulsants — 
Cerebral  Excitants — Delirifacients — Depressants — Morphine  Group. 
Alcohol-chloroform  Group:  Alcohol — General  Anaesthetics — Ether — Chlo- 
roform— Combined  Anaesthesia — Nitrous  Oxide — Ethyl  Bromide. 
Hypnotics  of  Alcohol-chloroform  Group :   Insomnia — Chloral — Other  Hyp- 
notics. 

Relationship  between  Constitution  and  Pharmacological  Action:  Theory 
of  Narcosis  (Meyer) — Other  Central  Depressants — Aconitine — Magnesium 
Salts — Bromides — Valerian. 

CHAPTER  III 

PHARMACOLOGY  OF  THE  SENSORY  NERVE-ENDINGS  (Gottlieb) 117 

Stimulants — Local  Anaesthesia — Cocaine — Substitutes  for  Cocaine. 

CHAPTER  IV 

PHARMACOLOGY  OF  THE  VEGETATIVE  NERVOUS  SYSTEM  (Gottlieb) 136 

The  Sympathetic  Nervous  System — Autonomic  or  Parasympathetic 
Nervous  System — Common  Reaction  to  Nicotine — Antagonistic  Func- 
tions of  the  Two  Systems — Epinephrin  a  "Sympathetic"  Drug — Auto- 
nomic Drugs. 

CHAPTER  V 

PHARMACOLOGY  OF  THE  EYE  (Meyer) 144 

Pharmacology  of  the  Retina — Of  the  Iris  and  Ciliary  Muscles — Central  My- 
driatics  and  Miotics — Peripheral  Miotics — Physostigmine — Pilocarpine — 
Other  Miotics — Peripheral  Mydriatics — Atropine — Substitutes  for  Atro- 
pine — Cocaine — Epinephrin — Astringents  and  Corrosives — Abrin — Dionin 
and  Peronin. 

CHAPTER  VI 

PHARMACOLOGY  OF  THE  DIGESTION  (Meyer) 162 

Pharmacology  of  the  Digestive  Glands:  Salivary  Secretion — Reflex  and 
Direct  Excitation — Inhibition — Elimination  by  Saliva — Gastric  Secretion — 
Stimulation  and  Inhibition — Pancreatic  Secretion — Internal  Secretion — 
The  Secretion  of  the  Bile — Cholagogues — Elimination  and  Antisepsis — 
Other  Liver  Functions — The  Secretion  of  the  Intestinal  Juice — Elimina- 
tion— Absorption  in  the  Alimentary  Canal — In  the  Stomach — In  the  Intes- 
tine— Absorption  of  Salts. 

Mechanics  of  Digestion:  Deglutition — Movements  of  the  Stomach — 
Emesis — Central  Emetics — Apomorphine — Peripheral  Emetics — Ipecac — 
Copper  Sulphate — Zinc  Sulphate — Tartar  Emetic — Treatment  of  Vomit- 
ing— Normal  Movements — Drugs  Stimulating  These — Inhibition  of  Gas- 
tric Movements — Atropine  and  Morphine. 


viii  CONTENTS 

Movements  of  Intestines:  Autonomic  Drugs — Sympathetic  Drugs — Atro- 
pine  and  Morphine. 

Cathartics:  Classification  —  Cathartics  Interfering  with  Absorption — Sa- 
lines— Calomel — Cathartics  Acting  on  Small  Intestine — Castor  Oil — 
Croton  Oil — Jalap,  Scammony,  Colocynth,  Gamboge,  Podophyllin — 
Cathartics  Acting  on  Large  Intestine — Senna,  Cascara,  Rhubarb,  Aloes, 
Phenolphthalein,  Sulphur — Carminatives. 
Obstipants — Astringents — Tannin — Metallic  Salts. 

CHAPTER  VII 

PHARMACOLOGY  OF  THE  REPRODUCTIVE  ORGANS  (Gottlieb) 218 

Nervous  and  Chemical  Correlation — Influence  of  Testicles  and  Ovaries — 
Erection — Yohimbin — Mammary  Glands — Lactogogues — Elimination  in 
Milk. 

Pharmacology  of  Uterine  Movements — Peripherally  Acting  Drugs — 
Oxytoxics,  Central  and  Reflex — Ergot — Hydrastis — Epinephrin — Hypo- 
physis Extracts. 

CHAPTER  VIII 

PHARMACOLOGY  OF  THE  CIRCULATION  (Gottlieb) 231 

Factors  Controlling  the  Circulation — Methods  of  Investigation. 
Pharmacology  of  the  Heart:  Cardiac  Functions — Actions  on  Centres  of 
the  Extracardial  Nerves — Drugs  Acting  on  Peripheral  Vagus — Nicotine — 
Choline  and  Muscarine — Atropine — Physostigmine — Actions  on  Accelera- 
tor in  Periphery — Cardiac  Depressants — Cardiac  Stimulants — Camphor — 
Ether — Alcohol — Epinephrin — Digitalis — Caffeine — Other  Factors. 
Pharmacology  of  the  Vessels:  Central  Vasoconstricting  Drugs — Caffeine,* 
Camphor,  etc. — Alcohol — Ether — Central  Vasodilating  Drugs — Amyl  Ni- 
trite— Peripheral  Vasoconstricting  Drugs — Epinephrin — Digitalis  Bodies — 
Peripheral  Vasodilating  Drugs — Capillary  Dilators — Yohimbin — Caffeine — 
Local  Applications. 

Pharmacology  of  the  Circulation  as  a  Whole:  Theory  of  the  Action  of 
Digitalis — Practical  Employment — Active  Principles — Chemical  Assay — 
Physiological  Assay — Cumulation — Dosage — Preparations — Treatment  of 
Cardiac  and  Vascular  Depression — Treatment  of  Vasoconstriction. 

CHAPTER  IX 

PHARMACOLOGY  OF  THE  RESPIRATORY  SYSTEM  (Meyer) 332 

Actions  of  CO2  and  O2 — Direct  or  Central  Stimulants — Respiratory  Seda- 
tives— Morphine — Expectorants — Treatment  of  Asthma. 

CHAPTER  X 

PHARMACOLOGY  OF  THE  RENAL  FUNCTION  (Meyer) 349 

Physiology  of  Diuresis — Factors  Controlling  Diuresis — Hydrsemia — Blood 
Flow  through  Kidney — Caffeine  Group — Digitalis  Group — Agents  Acting 
on  the  Tubules — Urinary  Antiseptics — Alkalies — Atophan. 

CHAPTER  XI 

PHARMACOLOGY  OF  THE  SECRETION  OF  SWEAT  (Gottlieb) 369 

Physiology — Diaphoretics,  Central  and  Peripheral — Antisudorifics. 

CHAPTER  XII 

PHARMACOLOGY  OF  THE  METABOLISM  (Meyer) 377 

General   Considerations — Increased   Assimilation — Altered   Metabolism — 


CONTENTS  ix 

The  Effects  of  Body  Temperature  and  of  Light  and  Radiant  Energy — 
Water  and  Salts  —  Alkalies — Acids  — Thyroid  —  Iodine  —  Quinine  —  Sub- 
stances, Inhibiting  Oxidation — Phosphorus — Arsenic — Antimony — Iron 
and  Mercury — Lecithin — Certain  Phases  of  Metabolism — Carbohydrate 
Metabolism — Purine  Metabolism. 

CHAPTER  XIII 

PHARMACOLOGY  OF  THE  MUSCLES  (Meyer) 422 

Physiology  "and  Anatomy — Strychnine — Muscular  Depressants — Stimu- 
lants— Caffeine — Alcohol — Alcohol  as  a  Food — Testicular  Extracts. 

CHAPTER  XIV 

PHARMACOLOGY  OF  THE  BLOOD  (Meyer) 435 

Infusions — Iron — Manganese  and  Arsenic — High  Altitudes — Agents  Affect- 
ing the  Leucocytes — Coagulation — Viscosity — Chemical  Composition  and 
Alkalinity — Toxicology  of  the  Blood — CO  and  HCN — Haemolysis. 

CHAPTER  XV 

PHARMACOLOGY  OF  HEAT  REGULATION  (Gottlieb) 453 

Physiology — Fever — Action  of  Antipyretics  in  Fever — Cold  Baths — Action 
of  Antipyretics  on  Heat  Production  and  Loss — Antipyrine  Group — Quinine 
— Salicylates — Other  Agents — Therapeutic  Employment — Quinine — Anti- 
pyrine Group — Salicylic  Acid  Group. 

CHAPTER  XVI 

PHARMACOLOGY  OF  INFLAMMATION  (Meyer) 481 

Nature  and  Significance  of  Inflammation — Cutaneous  Irritants — Exci- 
tants of  Inflammation — Vascular  Poisons — Caustics — Therapeutic  Em- 
ployment and  Mode  of  Action — Counterirritants — Vesicants  and  Sup- 
purants — Caustics  or  Escharotics — Inhibition  of  Inflammation — Analgesic 
Antiphlogistic  Agents — Astringents — Lime  Salts — Epinephrin — Quinine. 

CHAPTER  XVII 

ETIOTROPIC  PHARMACOLOGIOUJ  AGENTS  (Gottlieb) 497 

General  Antiseptics  and  Disinfection — Anthelmintics — Specific  Disinfec- 
tants— Creosote  in  Tuberculosis — Quinine  in  Malaria — Salicylic  Acid  in 
Rheumatism — Arsenical  Compounds  in  Protozoal  Diseases — Mercury  in 
Syphilis — Antitoxins — Vaccination  against  Rabies — Tuberculin — Serum 
Therapy — Toxins — Antitoxins — Ehrlich's  Side-chain  Theory — Antitoxic 
Sera — Tetanus — Diphtheria — Bacteriolysins — Agglutinins  and  Cytotoxms. 

CHAPTER  XVIII 

FACTORS  INFLUENCING  PHARMACOLOGICAL  REACTIONS  (Meyer) 561 

Solubility,  Quantity  and  Penetrating  Power  of  Drugs — Concentration  in 
the  Blood — Relation  between  Size  of  Dosage  and  Intensity  of  Effect — 
The  Functional  Condition  of  the  Organs — Antagonism — Distoxication — 
True  Antagonism — Immunity — Synergism — Hypersusceptibility — Anaphy- 
laxis — Experimental  Therapy — Clinic  and  Laboratory. 


ILLUSTRATIONS 

FIG.  PAGE 

1.  Upper  Part  of  M.  gracilis  Curarized,  Lower  Part  before  Operation 3 

2.  Diagrammatic  Representation  of  Spinal  Cord  (in  color) 15 

3.  Diagram  of  Intracentral  Inhibitory  Mechanism  of  Spinal  Cord  (in  color)  .  .  17 

4.  Forced  Inhalation  of  Irritant  Gas 61 

5.  Comparative  Effects  on  Blood-pressure  of  Chloroform  and  Ether 61 

6.  Sudden  Heart  Death  from  Administration  of  Concentrated  Chloroform  Vapor  65 

7.  Curve  Indicating  Depth  of  Sleep  and  Curves  Obtained  under  Paraldehyde .  .  87 
Diagram  of  Vegetative  Nervous  System  (in  color) 139 

8.  Nerves  and  Fibres  (in  color) 146 

9.  Monkey's  Eye  after  Atropine 149 

10.  Monkey's  Eye  after  Eserine 150 

11.  Innervation  of  Salivary  Glands  (hi  color) 162 

12.  Secretion  after  Taking  Food 170 

13.  Cat's  Stomach  Filled  with  Bismuth  and  Potato  Puree 189 

14.  Pharmacological  Action  on  Peripheral  Sympathetic  Organs  (hi  color) 191 

15.  Determination  of  Red-cell  Content  of  Blood  before  and  after  Administra- 

tion of  Salts 199 

16.  Sympathetic  Nerves  and  Nervus  Hypogastricus  (in  color) 221 

17a.  Normal,  Dicrotic,  and  Tense  Pulse 235 

17b.  Sphygmograms  from  Case  of  Lead  Colic 236 

18.  Williams'  Frog-heart  Apparatus 239 

19.  Experiments  on  Isolated  Mammalian  Heart  (Method  of  Hering  and  Bock)  241 

20.  Effect  on  Intestine  of  Stimulation  of  Splanchnic 243 

21.  Suppression  of  Muscarine  Standstill  by  Atropine 250 

22.  Circulatory  Action  of  Muscarine  in  Mammal 251 

23.  Suppression  of  Chloral  Standstill  by  Camphor  in  Perfused  Frog's  Heart .  . .  256 

24.  Effect  of  Epinephrin  on  Isolated  Cat's  Heart 260 

25.  Effect  of  Injection  of  Suprarenal  Extract  1  Minute  35  Seconds  after  Cessa- 

tion of  Heart-beat 261 

26.  Tracing  from  Frog's  Heart 263 

27.  Curves  Obtained  from  Surviving  Cat's  Heart 264 

28.  Increase  in  Variations  of   Intraventricular   Pressure  after   Strophanthin, 

and  Their  Progressive  Diminution 265 

29.  Effect  of  Strychnine  on  Blood-pressure  of  Curarized  Cat 273 

30.  Effect  Produced  by  Suprarenal  Extracts  on  Blood-pressure  and  Volume  of 

Different  Organs 281 

31.  Course  of  Vasoconstriction  Produced  by  Serum  from  Carotid  and  by  that 

from  Suprarenal  Veins 284 

32.  Effects  of  Strophanthin  on  Blood-pressure  and  on  Volume  of  Spleen  and  Leg  287 

33.  Blood-pressure    in  "Heart-lung"  Circulation    before    and    after    Digitalis 

Body 293 

34.  Blood-pressure  Curves  Showing  Effects  of  Digitalis  in  a  Dog 295 

35.  Changes  in  Ventricular  Volume  during  Cardiac  Cycle 297 

36a.  Tense  Pulse  before  and  after  Amyl  Nitrite 328 

37.  Pulse  during  Lead  Colic  and  after  Amyl  Nitrite 329 

38.  Antagonistic  Action  of  Morphine  and  Atropine  on  Respiration 336 

xi 


xii  ILLUSTRATIONS 

39.  Respiratory  Volume  with  Increasing  CO2  Tension  of  Blood 337 

40.  Urinary  Excretion  in  Dog  under  Varying  Blood-pressure 349 

41.  Secretion  of  Water  by  Tubules 353 

42.  Effects  of  Caffeine  on  Blood-pressure  and  Renal  Secretion  in  Chloralized 

Rabbit 361 

43.  Effects  of  Caffeine  on  Secretion  of  Normal  Right  and  Nerveless  Left  Kidney  362 

44.  45.  Heads  of  Calves'  Femur 406 

46.  Rabbit's  Femurs 410 

47.  Nerve  Stimulation  by  KC1 424 

48.  Contractions 426 

49.  Ergographic  Curves 429 

50.  Normal  and  Alcohol  Curves 430 

51.  Representation  of  Variation  in  Number  of  Red  Cells  in  the  Cu.  Mm 436 

52.  Influence  of  Fasting  on  Concentration  of  Blood 437 

53.  Influence  of  Alcohol  on  Concentration  of  Blood 437 

54.  Effect  of  Various  Altitudes  on  the  Number  of  Erythrocytes 445 

55.  Changing  Values  of  Head  Production  and  Output  Shown  as  Ordinates 457 

56.  Normal  Course  of  Puncture  Hyperthermia 464 

57.  Effect  of  Antipyrine  on  Puncture  Hyperthermia 464 

58.  Effects  of  Morphine  and  of  Antipyrine  on  Puncture  Hyperthermia 465 

59.  Antipyretic  Effect  of  Antipyrine 469 

60.  Antipyretic  Effect  of  Quinine 470 

61.  Tertian  Malarial  Parasites 528 

62.  63,  64 565 


PHARMACOLOGY 

CLINICAL  AND  EXPERIMENTAL 
CHAPTER  I 

PHARMACOLOGY  OF  THE  MOTOR  NERVE-ENDINGS 

WHILE  all  parts  of  the  nervous  system  may  be  influenced  by 
drugs,  the  nerve-endings  and  the  nerve-centres  are  much  more  sus- 
ceptible to  such  action  than  are  the  conducting  paths.  This  is  due 
partly  to  the  scanty  blood  supply  of  the  nerve-trunks,  but  chiefly  to 
the  fact  that  the  medullated  nerve-fibres  are  enclosed  in  sheaths  and 
are  thus  protected  from  the  action  of  the  drugs,  while  the  nerve- 
endings  are  not  thus  protected  and  are  therefore  more  readily  affected. 
However,  this  protection  is  not  absolute,  for,  when  exposed  nerve- 
trunks  are  moistened  with  solutions  of  drugs  or  exposed  to  volatile 
gases,  such  as  ether,  cholorofonn,  etc.,  which  are  soluble  in  the  lipoids 
of  the  medullary  portion  of  the  nerve,  stimulating  or  depressing 
actions  result  (Joteyko  u.  Stephanowska,  Sowton  and  Waller). 

DEPRESSION  OF  MOTOR  NERVE-ENDINGS 

Practically,  however,  pharmacological  action  on  nerve-trunks  is  of 
importance  only  when  a  concentrated  solution  of  a  drug  is  applied 
to,  or  in  the  immediate  neighborhood  of,  a  nerve,  as,  for  example, 
when  cocaine  is  purposely  so  injected,  or  when  a  hypodermic  of 
ether  chances  to  reach  a  nerve-trunk,  in  which  latter  case  most  un- 
desirable harmful  effects  may  result. 

After  discussion  of  the  pharmacology  of  the  motor  nerve-endings, 
that  of  the  central  nervous  system,  of  the  sensory  nerve-endings,  and 
finally  that  of  the  vegetative  nervous  system  will  be  taken  up  in  the 
order  named. 

CURARE  and  its  readily  analyzed  actions  form  a  good  starting- 
point  for  the  study  of  the  pharmacology  of  the  motor  nerve-endings. 
Although  little  or  not  at  all  used  in  therapeutics,  it  should  be  useful 
as  illustrating  certain  general  conceptions  of  pharmacological  action. 

The  South  American  arrow-poison,  curare  (woorari,  urari),  is 
obtained  from  various  poisonous  plants  of  the  family  of  Loganiaceae. 
Different  explorers,  notably  Humboldt  (1799-1804),  have  told  how 
the  Indians  prepared  this  substance  by  evaporating  aqueous  extracts 
of  various  plants,  often  adding  to  it  all  kinds  of  other  substances. 

They  also  reported  the  enormous  activity  of  the  freshly  prepared 
poison  when  it  is  introduced  into  wounds  of  men  and  animals. 

1 


*     'PHARMACOLOGY  OF  MOTOR  NERVE-ENDINGS 

Hifmboidt*  afeo  rioted  that- -the  flesh  of  animals  thus  poisoned  could 
be  eaten  with  impunity,  and  that  wounds  poisoned  by  curare  could 
without  danger  be  cleansed  by  sucking  out  the  poison.  Both  of 
these  observations  indicated  that  when  administered  by  the  stomach 
it,  as  a  rule,  was  inert. 

Active  Principles. — When  brought  to  Europe,  this  poison  immedi- 
ately greatly  interested  physiologists,  but,  owing  to  the  fact  that  its 
active  principles  readily  undergo  changes  resulting  in  a  diminution  of 
their  activity,  it  also  proved  far  less  powerful  than  the  fresh  curare. 

The  physiological  activity  of  curare  obtained  from  different  sources  has 
been  found  to  differ  not  only  quantitatively  but  also  qualitatively.  Bohm  * 
showed  that  different  alkaloids  are  contained  in  varying  proportions  in  the 
three  chief  commercial  varieties,  tube  curare,  pot  curare,  and  gourd  curare, 
thus  variously  named  from  the  different  containers  in  which  they  are  marketed. 
These  alkaloids  belong  to  two  groups,  the  curines,  possessing  little  or  no  true 
curare  action,  and  the  curarines,  which  produce  the  typical  effects.  The  curine 
from  tube  curare  is  a  cardiac  depressant,  and  as,  unfortunately,  most  of  the 
commercial  curare  is  of  this  variety,  its  unsatisfactory  action  is  readily  under- 
stood. 

Curarine  has  not  yet  been  obtained  in  crystalline  form.  Of  the  purest 
thus  far  prepared  (Bohm1)  1/100-1/50  of  a  milligram  produces  typical  par- 
alysis in  a  frog.  On  the  other  hand,  the  curines,  being  heart  poisons,  do  not 
produce  true  or  typical  curare  effects  but  cause  chiefly  other  disturbing  effects. 
The  more  curarine  and  the  less  curine  a  curare  contains,  the  more  typical  and 
uncomplicated  by  other  effects  is  its  action. 

When  an  effective  dose  of  curare  is  injected  into  a  frog,  it  soon 
drops  its  head,  abandons  its  normal  crouching  position,  and  lies  on 
its  belly.  At  first,  irritation  causes  a  powerful  muscular  response, 
but  soon  the  movements  become  weaker.  The  frog  no  longer  jumps, 
and  the  respiratory  movements  of  the  throat  muscles  are  the  only 
movements  observed  after  irritation.  Finally,  the  frog  becomes  en- 
tirely motionless  and  no  reflex  movements  result  from  even  the 
strongest  stimuli.  The  frog,  however,  is  not  dead,  for  the  heart  con- 
tinues to  beat  strongly.  It  is  simply  suffering  from  motor  paralysis 
and,  as  the  muscles  still  react  readily  to  a  direct  stimulation,  the 
cause  of  the  paralysis  must  lie  in  some  portion  of  the  nervous  system. 

Analysis  of  the  Actions. — In  the  middle  of  the  last  century, 
Claude  Bernard1  and  KolUker1  both  correctly  analyzed  these 
effects  and  determined  that  the  paralysis  was  of  peripheral  causation. 
By  ligature  of  the  iliac  artery  or  by  tightly  binding  the  whole  of  the 
upper  thigh,  exclusive  of  the  sciatic  nerve,  one  hind  leg  of  a  frog 
may  be  cut  out  from  the  circulation  and  the  blood  will  no  longer 
reach  the  periphery  in  this  limb,  although  its  innervation  is  not  dis- 
turbed. If  curare  be  injected  into  a  frog  so  prepared,  the  rest  of  the 
frog  soon  becomes  completely  paralyzed,  but  movements  occur  spon- 
taneously in  this  "isolated"  leg  and  reflexly  when  the  skin  of  any 
part  of  the  body  is  irritated.  Stimulation  of  the  cord  or  of  the 
exposed  sciatic  nerve  causes  muscular  contractions  in  this  leg  but 
not  in  the  other.  It  is  thus  shown  that  the  poison  does  not  act  on 
the  central  nervous  system,  but  must  produce  its  effects  by  acting 


CURARE  3 

on  the  nerves  in  the  periphery.  That  this  action  is  not  on  the  nerve- 
trunks  is  proved  by  the  fact  that  even  after  a  nerve-trunk  has  lain 
for  some  time  in  a  curare  solution  its  conductivity  is  not  impaired. 
It  must,  therefore,  be  concluded  that  the  drug  paralyzes  the  motor 
nerve-endings  of  voluntary  muscles  and  does  not  produce  any  action 
on  other  organs. 

It  is  of  interest  that  Fontana  (1781)  barely  failed  to  recognize  that  the 
action  of  curare  was  one  on  the  motor  nerve-endings.  However,  as  at  that  time 
the  existence  of  nerve-endings  had  not  been  realized  by  physiologists,  after  con- 
sidering the  hypothesis  that  this  drug  acted  on  the  lowest  portion  of  the 
motor  nerves,  he  discarded  it  and  located  the  curare  action  in  the  blood. 

The  sensory  nerve-endings  and  the  sensory  nerve-paths  are  not 
affected  by  curare,  for,  as  mentioned  above,  in  this  experiment  with 
the  "isolated"  leg,  irritation  of  any  part  of  the  body  which  had  been 
exposed  to  the  action  of  the  drug  causes  reflex  movements  in  the 
"isolated"  leg,  which  could  occur  only  if  the  sensory  nerve-endings, 
nerve-trunks,  and  the  sensory  tracts  and  the  reflex  mechanism  in  the 
cord  were  still  functionally  intact. 

The  curare  action,  therefore,  is  limited  to  the  motor  end-organs, 
and  the  motor  conduction  paths  remain,  certainly  for  a  time,  capable 
of  functioning. 

During  the  first  few  hours  of  the  action  of  curare,  that  the  very  delicate 
intermuscular  nerve-fibrils  do  not  lose  their  power  of  conduction,  was  shown 
by  Kuhne  l  in  ingenious  experiments..  He  succeeded  in  separating  a  muscle  into 
two  functionally  independent  parts  and  in  curarizing  the  upper  portion  while 
the  lower  portion  was  protected  by  a  tightly  bound  ligature.  As,  before  entering 
the  muscle,  the  nerve-trunk  divided,  sending  branches  to  supply  the  two  portions 
of  the  muscle,  if  the  law  of  "  conduction  of  impulses  in  both  directions  "  holds 
good  under  these  conditions,  it  should  be  possible  for  a  stimulation  of  the 
nerve-fibres  starting  in  the  poisoned  part  of  the  muscle  to  pass  up  these  fibres 
to  the  parent  trunk  and  thence  down  the  branch  leading  to  the  unpoisoned  part 
of  the  muscle  and  to  cause  contraction  of  this  part.  As  a  matter  of  fact,  in 
these  experiments  stimulation  of  the  intramuscular  filaments  of  the  nerve  in  the 
poisoned  half  promptly  and  regularly  caused  contraction  in  the  unpoisoned 
muscle.  (Fig.  1.) 

The  motor  conduction  paths  are  affected  only 
after  long-continued  exposure  to  curare  solu- 
tions (Kuhne,1  Herzen,  v,  Bezold),  but  this  is 
of  absolutely  no  importance  except  in  the  frog. 

It  thus  appears  that  curare  interposes  to 
centrifugal  impulses  a  resistance  at  a  point  be- 
tween the  motor  nerve-fibres  and  their  final  ter- 
minal organs  in  the  muscles,  a  resistance  which 
cannot  be  overcome  if  the  curare  action  be  fully 
developed.  During  the  early  stages  of  the  ac- 
tion, this  growing  resistance  manifests  itself  by 
a  progressive  tendency  to  fatigue  of  the  motor 
nerve-endings,  so  that  under  rhythmic  stimula-  FIG.  I.—L,  upper  part  of 
tion  the  contractions  grow  shorter  and  shorter  f,ei^ef.rap^t 
(Bohm,2  Santesson1).  rized- 


4          PHARMACOLOGY  OF  MOTOR  NERVE-ENDINGS 

As  is  to  be  expected  the  results  of  the  paralysis  caused  by  curare 
differ  materially  in  frogs  and  in  warm-blooded  animals.  Curarized 
frogs  can  continue  to  live  for  days,  for,  even  after  all  respiratory 
movements  have  ceased,  the  respiration  through  the  skin  can  supply 
all  the  oxygen  necessary  for  their  metabolism.  A  satisfactory  circu- 
latory function  is  maintained  and  renal  secretion  continues  and  at- 
tends to  the  elimination  of  the  poison.  Curare  poisoning  may,  there- 
fore, be  caused  in  a  second  frog  by  injecting  the  urine  of  a  curarized 
one  (Jdkabhdzy). 

Only  much  larger  doses  (30  times  that  necessary  to  cause  paralysis)  are 
fatal  in  frogs,  these  larger  doses  interfering  with  the  circulation  and  thus 
preventing  the  secretion  of  the  urine  and  the  elimination  of  the  poison.  Tillie 
observed  recovery  from  a  paralysis  which  had  been  induced  by  smaller  doses 
and  had  lasted  25  days. 

In  mammals  the  results  of  this  primary  action  of  curare  are  quite 
different,  for  in  them  the  muscular  paralysis  causes  asphyxia  and 
death  unless  artificial  respiration  is  instituted.  However,  the  respira- 
tory muscles  are  the  last  to  be  affected,  so  that,  by  administering  the 
proper  dose,  it  is  possible  to  keep  a  rabbit  alive  for  hours  with  all 
its  muscles  paralyzed  except  the  diaphragm. 

If  artificial  respiration  is  maintained  and  the  curare  be  of  good 
quality,  both  heart  and  vessels  are  entirely  unaffected  by  any  but 
very  large  doses,  and,  as  the  poison  is  excreted  through  the  kidneys 
fairly  rapidly,  mammals  too  may  recover  after  the  paralysis  passes 
off.  Only  after  larger  doses  are  other  functions  than  those  of  the 
motor  nerve-endings  affected.  Very  large  doses  lower  the  blood- 
pressure  by  a  depressing  action  on  the  peripheral  vasoconstrictor 
mechanism  (Tillie).  When  this  action  is  fully  developed,  neither 
stimulation  of  the  sciatic  nor  asphyxiation  causes  a  rise  in  the  blood- 
pressure.  Large  doses  also  weaken  the  cardio-mhibitory  action  of  the 
vagus,  but  the  motor  mechanism  of  the  heart  is  unaffected.  The 
motor  nerve-endings  of  smooth  muscle  are  also  but  little  affected 
(Bidder),  the  intestine  remaining  excitable  and  peristalsis  continu- 
ing even  after  extremely  large  doses. 

In  connection  with  its  use  in  physiological  experiments,  the  ques- 
tion as  to  the  nature  of  the  action  of  curare  on  the  central  nervous 
system  is  of  great  interest.  In  Steiner's  experiments  with  fishes,  a 
narcosis  of  the  cerebrum  was  apparently  induced,  but  it  is  doubtful 
if  the  cerebrum  of  higher  animals  is  appreciably  affected  by  curare. 
The  spinal  cord  is  certainly  not  depressed.  On  the  contrary,  accord- 
ing to  Tillie,  larger  doses  cause  an  increase  in  its  reflex  excitability 
similar  to  that  caused  by  strychnine.  In  mammals  an  increase  in  the 
excitability  of  the  vasomotor  centre  occurs  quite  early  (Sollmann  and 
Pilcher) . 

The  effects  of  curarization  on  the  temperature  and  metabolism  (0.  Frank 
tt.  F.  Voit)  £re  to  be  considered  simply  as  a  result  of  the  abolition  of  the 


CURARE  5 

activity  of  all  voluntary  muscles.  Glycosuria,  which  has  been  observed  both  in 
animals  and  in  man  after  injections  of  curare,  is  an  inconstant  phenomenon 
depending  on  unknown  causes  (Morishima). 

It  has  long  been  known  that  curare  administered  orally  is  entirely 
ineffective,  even  when  given  in  doses  much  larger  than  those  which 
are  lethal  when  given  hypodermically.  Formerly  this  lack  of  action 
when  the  drug  was  thus  administered  was  explained  by  the  assump- 
tion that  the  acid  gastric  juice  destroyed  or  changed  the  curare. 
Although  the  acid  of  the  gastric  juice  has  a  deleterious  action  on  the 
easily  decomposed  curarin  (N.  Zuntz),  this  is  not  pronounced  enough 
to  explain  the  great  difference  between  the  action  of  the  drug  when 
given  by  mouth  and  when  injected  subcutaneously.  Nor  is  it  due  to 
its  not  being  absorbed  from  the  alimentary  canal.  Bernard2  and 
Hermann  both  showed  that  the  comparatively  slow  absorption  from 
the  alimentary  canal  and  the  comparatively  rapid  excretion  by  the 
kidneys  account  for  the  lack  of  action  when  the  drug  is  administered 
orally,  for,  if  the  renal  arteries  be  ligatured  and  the  drug  then  in- 
troduced into  the  stomach,  typical  curare  effects  develop-. 

GENERAL  FACTORS  AND  PRINCIPLES   INVOLVED  IN  THE 
PHARMACOLOGICAL  ACTION  OF  POISONS  AND  DRUGS 

Before  going  farther,  it  seems  advisable  to  bring  forward  certain 
general  factors  and  principles  involved  in  the  pharmacological  action 
of  poisons  and  drugs. 

By  the  action  of  a  drug  or  poison  we  understand  the  aggregate 
of  the  alterations  which  it  causes  in  the  functions  of  the  whole  body. 
The  action  of  curare  is  directed  with  unusual  precision  against  a 
single  kind  of  organ,  the  motor  nerve-endings.  This  we  call  an 
ELECTIVE  action.  When  injected  subcutaneously,  curare  does  not 
act  on  the  subcutaneous  tissues  at  the  point  of  injection,  nor,  when 
given  intravenously,  does  it  act  on  the  blood-vessels.  It  has  thus  no 
local  action,  but  the  motor  nerve-endings  in  the  whole  body  are 
acted  upon  wherever  sufficient  amounts  of  the  drug  are  carried  by  the 
blood.  This  we  call  SYSTEMIC  action. 

Just  as  the  ordinary  dose  affects  only  the  motor  nerve-endings, 
so  too  the  action  of  a  dose  many  times  larger  is  limited  to  these  same 
organs,  all  other  cells  in  the  body  being  unaffected  or  nearly  so. 

With  many  other  drugs  having  an  elective  systemic  action,  we 
find  a  somewhat  different  behavior;  for  example,  with  an  increase 
of  that  minimal  dose  of  atropine  which  diminishes  glandular  secretion, 
the  pupils  dilate  and  the  pulse-rate  increases,  and,  after  a  somewhat 
greater  increase  in  the  dose,  still  other  functions  are  affected.  Here 
the  first  effect  is  soon  followed  by  effects  due  to  actions  on  other 
organs,  while  with  curare  the  systemic  action  (except  with  very  large 
doses)  is  exerted  on  a  single  kind  of  organ,  as  it  is  in  a  very  high 
degree  elective.  Curare  also  illustrates  well  how  the  results  of  the 


6          PHARMACOLOGY  OF  MOTOR  NERVE-ENDINGS 

same  pharmacological  action  may  differ  in  different  species  of  animals, 
the  frog  surviving  for  days  in  spite  of  complete  paralysis  of  all  volun- 
tary muscles,  whereas,  in  warm-blooded  animals,  asphyxia  results  from 
this  identical  action.  Here  we  have  illustrations  of  PRIMARY  or  DIRECT, 
and  SECONDARY  or  REMOTE  or  INDIRECT  pharmacological  actions  or 
illustrations  of  pharmacological  actions  and  their  effects. 

THE  NATURE  OF  PHARMACOLOGICAL  ACTIONS 

The  analysis  of  the  curare  action  as  given  above  consists  in  a  de- 
termination of  its  seat  of  action  in  a  physiological  sense,  such  deter- 
mination of  the  seat  of  action  being  always  the  first  problem  in 
pharmacological  research.  The  nature  of  the  action  in  the  case  of 
curare  paralysis,  as  also  in  the  case  of  all  other  pharmacological  ac- 
tions, is  to  be  considered  as  a  chemical  or  physico-chemical  interaction 
between  the  drug  and  the  constituents  of  the  cell.  In  the  case  of  curare, 
as  in  most  cases,  it  is  not  yet  known  which  elements  of  the  functioning 
cell  are  involved  in  the  reactions.  However,  this  lack  of  precise 
knowledge  in  no  way  affects  the  conception  that  assumes  a  chemical 
or  physical  change  in  the  affected  organs  whenever  a  pharmacological 
action  takes  place.  In  some  instances  it  is  known  with  what  cell 
elements  the  drug  reacts;  for  example,  in  the  case  of  the  action  of 
carbon  monoxide  on  the  blood-cells,  it  is  the  haemoglobin  which  enters 
into  the  chemical  reaction.  In  other  cases  the  chemical  properties  of 
the  drug  enable  us  to  deduce  with  considerable  precision  the  chemical 
substances  in  the  cell  which  are  especially  involved  in  the  chemical 
reaction  occurring.  In  this  way  the  cytotoxic  action  of  oxalic  acid 
has  led  to  a  recognition  of  the  importance  of  the  calcium  salts  for 
cell  life.  In  the  case  of  the  alkaloids,  on  the  other  hand,  we  know 
only  the  place  where  the  reaction  takes  place  but  not  the  reacting 
constituents  of  the  protoplasm. 

Even  in  the  analysis  of  the  action  of  curare,  it  must  be  admitted 
that  the  determination  of  the  seat  of  action  is  not  absolutely  definite, 
for  the  nervous  end-organs  are  complex  structures  containing  nerve- 
fibrils  which  pass  into  the  true  end-organs,  the  nerve-plates,  these  last 
finally  send  branching  filaments  into  the  muscle-cells  (Herzen,  Joteyko, 
Langley). 

In  all  cases  an  alteration  of  the  protoplasm  must  be  assumed, 
and  we  must  conceive  that  this  protoplasm  attracts  to  itself  the  drug 
present  in  a  definite,  although  very  moderate,  concentration  in  the 
blood.  Curare  gives  us  a  good  example  of  this  dependence  of  the 
reaction  between  the  protoplasmic  constituents  and  the  drug  on  a 
definite  adequate  concentration  of  the  drug  in  the  blood  and  the 
tissue  fluids,  the  so-called  "threshold  value."  If,  after  subcutaneous 
or  intravenous  injection,  the  concentration  of  the  drug  in  the  blood 
reaches  this  adequate  concentration  rapidly  enough,  the  chemical  or 


CURARE  7 

physical  reaction  occurs  and  the  pharmacological  reaction  results.  If, 
however,  the  same  dose  distributes  itself  throughout  a  larger  animal, 
or  if  it  enters  the  blood  gradually  and  at  the  same  time  is  removed 
from  it  by  the  activity  of  excretory  organs,  as  for  example  when 
curare  is  absorbed  from  the  stomach  and  excreted  by  the  kidney,  then 
this  adequate  concentration  in  the  blood  is  not  attained  and  the 
pharmacological  action  does  not  occur. 

Once  the  curare  has  combined  with  the  nerve-endings  it  remains 
combined  for  a  considerable  time  notwithstanding1  its  rapid  disap- 
pearance from  the  blood.  Here,  too,  in  the  stability  of  this  combination, 
we  have  the  expression  of  a  chemical  or  physico-chemical  affinity  be- 
tween the  protoplasmic  elements  and  the  drug,  but  we  have  no  exact 
knowledge  of  the  nature  of  this  affinity.  At  first  sight  the  gradual 
disappearance  of  the  curare  paralysis  appears  quite  as  puzzling  as  its 
development.  In  CO  poisoning  the  return  of  function  is  explained 
by  the  dissociation  of  the*  CO  haemoglobin,  which  begins  as  soon  as 
the  partial  pressure  of  the  CO  in  the  blood-plasma — i.e.,  the  concentra- 
tion in  the  neighborhood  of  the  susceptible  cell — diminishes  below  a 
certain  level  or  is  reduced  to  zero.  In  a  similar  manner — that  is,  by 
the  conception  of  the  combination  of  the  drug  with  the  cell  sub- 
stance as  a  reversible  process — we  must  explain  the  gradual  return 
of  function  in  other  cases,  which  have  thus  far  not  been  capable  of 
closer  analysis  (Bo'hm2). 

Therapeutic  Use  of  Curare.  — Many  attempts  have  been  made 
to  use  curare  therapeutically,  but  without  success.  It  might  appear 
that  it  would  be  advantageous  to  use  it  to  prevent  convulsions  due  to 
an  abnormal  excitability  of  the  central  nervous  system.  Inasmuch  as 
the  respiratory  muscles  are  the  last  to  be  paralyzed,  it  is  possible,  at 
least  in  experiments  on  animals,  to  maintain,  even  without  artificial 
respiration,  a  degree  of  curare  action  which  prevents  ordinarily  effec- 
tive doses  of  strychnine  from  causing  convulsions.  Such  treatment 
of  strychnine  poisoning,  although  entirely  symptomatic,  if  combined 
with  the  removal  of  the  poison  by  means  of  stomach  lavage  and  with 
stimulation  of  diuresis,  might  be  the  means  of  saving  life,  for  ex- 
haustion of  the  vitally  important  nervous  centres  may  result  from  the 
convulsions.  In  man,  too,  by  prevention  of  convulsions  by  the  use  of 
curare,  life  might  be  saved  in  those  cases  of  tetanus  and  rabies  where 
the  body  is  able  to  overcome  the  infection.  As  a  matter  of  fact, 
in  a  number  of  such  cases,  a  cessation  or  diminution  of  the  force  and 
frequency  of  the  convulsions  has  followed  the  use  of  curare  (L.  Vella, 
Busch,  F.  A.  Hoffman,  Bergell  in  tetanus,  Offenberg,  Penzoldt  in 
rabies.)  If  this  treatment  be  adopted,  a  complete  paralysis  of  all  the 
motor  nerve-endings  must  be  avoided,  for,  if  the  respiratory  muscles 
be  paralyzed,  long-continued  artificial  respiration  will  be  necessary 
and  this  alone  can  jeopardize  life.  Unfortunately,  owing  to  the 


8          PHARMACOLOGY  OF  MOTOR  NERVE-ENDINGS 

differences  in  the  activity  of  different  specimens  of  curare  and  their 
tendency  to  deteriorate,  even  physiologically  assayed  preparations 
cannot  be  used  with  any  certainty  as  to  dosage. 

Many  other  substances  resemble  curare  in  their  action,  and  in 
their  study  certain  interesting  relationships  between  chemical  con- 
stitution and  physiological  action  have  come  to  light. 

The  characteristic  action,  of  almost  all  ammonium  bases  is  the  paralysis 
of  motor  nerve-endings.  This  is  not  possessed  by  chloride  of  trimethyl-ammonium, 
a  tertiary  base  (Santesson  u.  Koraen),  but  the  salts  of  tetramethyl-ammonium 
and  those  of  the  tetraethyl-ammonium  (Rabuteau,  Jodlbauer,  Jordan),  in  ac- 
cordance with  the  quadrivalency  of  these  bases,  possess  this  action.  Moreover, 
in  the  case  of  many  alkaloids,  such  as  strychnine,  morphine,  quinine,  etc.,  their 
transformation  into  tetrabasic  substances,  such  as  methylstrychnine,  methyl- 
morphine,  etc.,  endows  them  with  a  more  or  less  marked  curare  action  (Brown 
and  Fraser).  In  this  connection,  it  is  of  interest  that  curarin  is  tetrabasic,  while 
curine,  which  does  not  possess  this  characteristic  action,  is  tribasic,  but  acquires 
it  when  methylated. 


x 
H3C~N,  trimethylamine,  a  tertiary  base. 


AN,  -  1,  trimethylamine  hydroiodate. 
H,C/    I 

H 

\  TTQ^v^ 

-^N  +  ICHs  =Tic\^'>m  —  I)  tetramethylammonium  iodide,  a  quaternary  base. 


Alkaloid.  Alkaloid. 


Hj 


+1011,=  N 

CHj  CHj 

Tertiary  Quaternary 

combination.  combination. 

It  would  appear,  therefore,  that  the  power  of  paralyzing  motor  nerve- 
endings  is  a  property  possessed  especially  by  quaternary  bases.  This  is  ap- 
parently not  due  to  their  containing  certain  elements  or  groups,  but  rather  to 
the  increased  basicity  resulting  from  the  change  from  a  tertiary  to  a  quaternary 
base  (Fiihner),  for  the  analogous  bases,  which  in  place  of  nitrogen  contain 
arsenic  (Biirgi),  antimony,  phosphorus  (Vulpian,  Lindemann),  iodine  (Gottlieb), 
or  sulphur  (Curd),  (arsonium,  stibonium,  phosphonium,  ionium,  and  sulfine 
bases),  act  like  curare.  It  would  be  a  mistake,  however,  to  conclude  that  only 
this  especial  type  of  base  possesses  curare  action,  for  the  same  action  is  exerted 
by  a  group  of  bases  which  are  not  quadrivalent  (chinoline,  pyridine,  piper  idine, 
and  others)  (Moore  and  Prow),  while  non-basic  substances,  —  e.g.,  camphor  in 
the  frog,  —  and  lastly  certain  poisons  of  animal  origin,  such  as  the  venom  of  the 
cobra  and  of  the  spectacled  snake,  also  produce  curare-like  actions  (Vollmer, 
Arthus).  It  is,  however,  probable  that  these  substances,  which  are  chemically  so 
different,  do  not  all  act  on  the  same  elements  or  substances  in  the  nerve- 
endings  but  on  chemically  different  substances  or  elements  in  them. 


STIMULANTS  OF  MOTOR  NERVE-ENDINGS  9 

STIMULATION  OF  MOTOR  NERVE-ENDINGS 

The  motor  nerve-endings  in  striped  muscles  are  also  susceptible 
of  excitation  by  chemical  substances.  This  has  long  been  known 
of  guanidin  (Gergens  u.  Baumann),  while  the  fibrillary  muscular 
twitchings  caused  by  physostigmine  are  also  due  to  excitation  of  the 
motor  nerve-endings  (Rothberger).  Of  especial  interest  is  the 
reciprocal  antagonism  of  curare  and  physostigmine  (Rothberger,  Pal). 
Animals  poisoned  by  curare  to  the  degree  of  complete  cessation  of 
respiratory  movements,  in  which  indirect  muscle  excitability  (by 
centripetal  stimulation  of  the  sciatic)  has  disappeared,  after  the 
intravenous  administration  of  physostigmine,  show  spontaneous  res- 
piratory movements  and  normal  muscle  excitability,  while  the  adminis- 
tration of  a  fresh  dose  of  curare  again  brings  about  complete 
paralysis. 

One  could  think  of  this  play  of  antagonism  between  these  two 
drugs  as  resulting  as  follows: 

As  physostigmine  possesses  a  similar  affinity  for  the  nerve-endings, 
it  displaces  curare  from  its  combination  with  these  structures.  Ac- 
cording to  the  doses  administered, — that  is,  in  accordance  with  the 
effective  amounts  present  in  the  cells, — the  opposite  action  may  occur, 
curare  replacing  the  physostigmine.  It  is,  however,  also  possible  that 
the  two  drugs  act  in  different  places  or  on  different  substances  in  the 
terminal  nervous  organs,  and  that  curare  places,  as  it  were,  a  resist- 
ance coil  in  the  end-plates  while  physostigmine  increases  the  excita- 
bility of  still  more  peripherally  situated  portions  of  the  terminal 
organs.  If  the  latter  hypothesis  represents  the  facts,  a  motor  impulse, 
although  able  to  pass  through  a  portion  of  the  end-organ  which  had 
been  rendered  more  resistant  by  curare,  would  reach  the  terminal 
portion  of  the  nerve  in  the  muscle-cell  only  in  such  diminished  force 
as  not  to  cause  an  effective  excitation.  If,  however,  these  terminal 
portions  had  been  rendered  more  excitable  by  physostigmine,  even 
the  weakened  impulse  would  produce  an  effect,  while  a  further  in- 
crease of  the  interposed  resistance,  resulting  from  further  dosage  with 
curare,  would  prevent  entirely  the  passage  of  motor  impulses  to  this 
terminal  portion  or  weaken  them  to  such  a  degree  that  they  would  no 
longer  be  effective.  Certain  other  bases,  among  them  choline,  over- 
come the  curare  paralysis  by  an  action  similar  to  that  of  physostigmine 
(Rothberger,  Pal). 

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10         PHARMACOLOGY  OF  MOTOR  NERVE-ENDINGS 

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CHAPTER  II 

PHARMACOLOGY  OF  THE  CENTRAL  NERVOUS  SYSTEM 

IN  the  study  of  the  pharmacology  of  the  motor  nerve-endings,  it 
has  been  shown  that  in  these  nerves  the  capacity  of  transmitting 
centrifugal  impulses  to  the  muscle-cells  may  be  depressed  or  dimin- 
ished by  curare  or  increased  by  other  substances.  In  all  other  nervous 
organs  also  and  especially  in  the  nervous  centres,  drugs  and  poisons 
may  cause  STIMULATION  or  DEPRESSION,  but  never  a  qualitative  change 
of  function.  However,  although  pharmacological  actions  in  the  cen- 
tral nervous  system  may  consist  only  in  depression  or  stimulation 
of  nervous  elements,  it  would  be  a  mistake  to  conclude  that  there 
can,  therefore,  be  but  two  types  of  pharmacologically  active  sub- 
stances, of  which  one  increases  while  the  other  depresses  the  activity 
of  the  whole  central  nervous  system,  as  exemplified  by  the  old 
classification  of  sedatives  and  excitants. 

Different  drugs,  even  though  acting  on  the  central  nervous  system 
in  but  one  sense,  differ  much  from  each  other  on  account  of  differ- 
ences in  the  order  in  which  their  actions  on  different  functions  de- 
velop, this  order  being  characteristic  for  each  drug  or  group  of  drugs. 
Owing  to  the  different  susceptibility  of  different  parts  of  the  central 
nervous  system  to  each  individual  drug,  there  results  a  great  variety 
in  the  effects  which  may  be  produced. 

Often  certain  parts  are  so  much  more  susceptible  to  the  action  of 
a  drug  than  all  other  parts  of  the  central  nervous  system,  that  from 
a  therapeutic  point  of  view  only  the  action  of  this  portion  need  be 
considered.  For  example,  apomorphine  in  certain  dosage  acts  directly 
only  on  the  vomiting  centre,  leaving  all  other  parts  of  the  central 
nervous  system  practically  unaffected,  while  small  doses  of  morphine 
act  almost  exclusively  on  the  function  of  pain  perception  (probably 
located  in  the  cerebral  cortex)  and  on  the  respiratory  centre,  its 
numerous  other  actions  on  the  other  centres  resulting  only  from  larger 
doses.  Quite  as  sharply  limited  are  the  primary  effects  of  numerous 
other  drugs,  and,  as  a  result  of  the  differences  in  the  sensibility  of 
the  different  elements  which  are  affected,  the  whole  picture  of  the 
pharmacological  action  of  each  drug  is  distinguished  by  the  char- 
acteristic order  in  which  changes  occur  in  the  different  functions. 

The  wonderful  number  of  varieties  of  drug  actions  is  also  due 
to  the  fact  that  different  parts  of  the  central  nervous  system  may  not 
only  differ  quantitatively  in  their  susceptibiliy  to  a  given  drug,  but 
also  to  the  fact  that  often  enough  certain  centres  may  be  excited  and 
others  depressed  by  identical  doses  of  a  given  drag.  Such  a  combina- 
tion of  depression  of  certain  functions  and  stimulation  of  others 

11 


12     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

is  very  commonly  caused  by  toxic  doses  of  those  drugs  which  act 
especially  on  the  central  nervous  system.  Conditions  varying  from 
those  resembling  tipsiness  with  moderate  excitement  to  those  with 
most  violent  delirium  or  convulsions  or  with  complete  loss  of  con- 
sciousness are  examples  of  such  pharmacological  actions,  and  are 
observed,  for  example,  in  atropine  or  in  camphor  poisoning. 

Numerous  poisons  have  the  peculiar  property  of  causing,  in  the  later 
stages  of  their  action,  or  in  larger  dosage,  a  depression  of  those  very  cen- 
tres which  they  primarily  stimulate.  The  action  of  prussic  acid  on  the 
respiratory  centre  is  a  typical  example  of  such  behavior.  Such  observa- 
tions have  occasioned  much  discussion  as  to  whether  or  not  this  is  a  gen- 
eral law, — that  is,  whether  every  chemical  irritation  must  in  the  begin- 
ning cause  a  stimulation.  Inasmuch  as  no  increase  in  the  excitability  of 
the  nerve-endings  can  be  observed  at  the  commencement  of  the  curare 
action  nor  in  that  of  the  respiratory  centre  at  the  beginning  of  the 
morphine  action,  it  is  not  possible  to  conclude  that  this  is  a  universal 
rule.  The  qualitative  differences  in  the  reactions  and  the  quantita- 
tive differences  in  the  susceptibility  of  the  different  but  functionally 
related  tracts  of  the  central  nervous  system  may  be  explained  by  the 
justifiable  assumption  that  their  protoplasm  possesses  different 
chemical  and  physical  affinities  for  different  drugs.  However,  our 
knowledge  of  the  chemical  physiology  of  the  central  nervous  system 
is  too  incomplete  to  permit  even  rough  guesses  as  to  the  nature  of 
these  affinities.  From  these  differences  in  their  chemical  behavior 
toward  the  different  drugs,  it  may  be  concluded  that  probably  each 
nervous  protoplasmic  element  which  possesses  a  special  function  has 
certain  peculiarities  in  its  composition.  The  elective  absorption  of 
dyes — e.g.,  the  vital  staining  with  methylene  blue — is  a  visible  demon- 
stration of  such  differences  in  the  affinities  of  different  elements  of  the 
central  nervous  system. 

From  the  above,  it  is  evident  that  the  ANALYSIS  OP  PHARMACO- 
LOGICAL ACTIONS  IN  THE  CENTRAL  NERVOUS  SYSTEM  Will  Consist  mainly 

of  a  determination  of  the  points  or  functions  acted  upon,  and  of  the 
order  in  which  the  different  ones  are  affected.  It  seems  well  to  start 
with  a  consideration  of  a  stimulating  pharmacological  action,  that  of 
strychnine. 

STRYCHNINE 

• 

Strychnine  and  a  second  much  less  active  alkaloid,  brucine,  occur 
chiefly  in  various  strychnos  varieties  (order  Loganiacese)  and  especi- 
ally in  the  seeds,  wood,  and  bark  of  Strychnos  Nux-vomica,  indigenous 
in  Southern  Asia.  Nux  vomica,  the  dried  seed  of  this  tree,  contains 
about  1.3  per  cent,  of  strychnine  and  1.7  per  cent,  of  brucine. 

The  bark  contains  even  larger  quantities  of  brucine,  while  the 
seeds  of  Strychnos  ignatii,  S.  tieute,  and  other  strychnos  varieties 
contain  as  much  as  2  per  cent,  of  strychnine  and  also  brucine.  Some 
Malay  tribes  have  used  these  in  the  preparation  of  arrow-poisons. . 


STRYCHNINE  13 

Strychnine  itself  is  an  alkaloid,  crystalline,  efflorescent,  and  odor- 
less, but  with  a  very  bitter  taste.  It  is  poorly  soluble  in  water  and 
may  be  extracted  from  it  by  chloroform.  Its  salts  are  readily  soluble 
in  water,  the  sulphate  being  the  one  most  used.  When  dissolved  in 
concentrated  H2SO4,  strychnine  gives,  on  addition  of  a  trace  of 
potassium  bichromate,  a  violet  color,  which  changes  gradually  to 
blue  and  then  to  green. 

The  DOMINANT  ACTION  OF  STRYCHNINE  is  essentially  an  elective  one 
on  the  reflex  arcs  in  the  central  nervous  system.  If  the  reflexes  are 
depressed  as  a  result  of  pathological  conditions,  small  doses  of  strych- 
nine may  restore  them  to  their  normal  condition,  while  toxic  doses 
cause  such  an  exaggerated  irritability  of  the  reflex  mechanism  that  a 
reflex  causes  not  only  the  ordinarily  resulting  normally  coordinated 
movements  occurring  with  abnormal  intensity,  but  also  other  similarly 
exaggerated  movements  not  normally  resulting  from  such  reflex. 
Normally,  excitation  of  reflexes  in  the  cord  causes  responses  of 
various  sorts,  occurring  according  to  fixed  laws,  so  that,  after  stimula- 
tion of  a  given  sensory  nerve,  certain  movements  and  combinations 
of  movements  occur.  When  the  action  of  strychnine  has  fully  de- 
veloped, however,  each  single  stimulus  affecting  the  sensory  organs 
causes  a  simultaneous  contraction  of  all  the  skeletal  muscles. 

ACTION  IN  THE  FROG. — If  1/10  to  2/10  mg.  of  strychnine  be  in-\ 
jected  into  a  frog,  he  soon  shows  an  abnormal  reaction  whenever  he 
is  touched.  While  a  normal  frog,  if  lightly  touched,  does  not  move 
at  all,  and  responds  to  stronger  'tactltte  stimuli  only  when  they  affect 
especially  sensitive  parts,  after  strychnine  the  very  lightest  touch  is 
enough  to  cause  violent  reflexes.  Slight  shaking,  which  ordinarily 
is  without  effect,  causes  a  pronounced  muscular  response,  for  the  ex- 
citability of  the  reflex  mechanism  has  been  increased.  Finally,  any 
sensory  stimulus  produces  a -tetanic  convulsion. 

By  TETANUS  is  meant  a  tonic  contraction  of  all  the  skeletal  muscles, 
lasting  seconds  or  minutes,  which  is  caused  by  a  rapid  succession  of 
single  muscular  contractions.  The  individual  convulsions  may  be 
separated  from  each  other  by  longer  or  shorter  periods,  which,  how- 
ever, may  be  so  short  that  for  a  considerable  period  the  body  remains 
absolutely  stiff  and  motionless.  Inasmuch  as,  when  all  the  muscles 
contract  simultaneously,  the  extensors  overcome  the  flexors,  the  ex- 
tremities and  the  trunk  both  assume  the  position  of  ^tension. 

A  frog  may  lie  for  many  days  in  this  condition,  as  the  respiration  j 
through  the  skin  suffices  for  its  sluggish  metabolism,,  and  as  the 
tetanus  itself,  even  when  long  continued,  does  not  kill  the  frog.  When 
produced  by  other  poisons,  such  as  tetanus  toxine  or  certain  poly- 
sulphides  (Harnack),  the  tetanus  may  last  for  weeks  and  the  frog 
continue  to  live.  Small  doses  of  strychnine  also  may  cause  a  con- 
dition of  maximally  increased  reflex  excitability  which  lasts  for  from 
8  to  14  days,  during  which  every  stimulus  excites  a  tonic  convulsion 


14         PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

(Bongers}.  As  somewhat  larger  doses  of  strychnine  rapidly  cause 
death  in  frogs,  it  is,  therefore,  clear  that  the  fatal  result  is  due  not 
to  the  tetanus  itself,  but  to  other  actions  of  strychnine  which  will  be 
discussed  later. 

A  closer  ANALYSIS  OF  THE  ACTION  shows  that  its  seat  is  in  the 
cord.  Its  central  nature  is  demonstrated  by  the  fact  that  a  leg  isolated 
from  the  circulation  before  the  injection  of  the  drug  is,  like  the 
others,  involved  in  the  convulsions,  while  as  soon  as  its  nerves  are 
severed  this  is  no  longer  the  case  (J.  Mutter,  Kolliker).  The  con- 
vulsions in  a  decerebrated  frog  differ  in  no  way  from  those  in  an  intact 
one,  but,  on  the  other  hand,  if  the  spinal  cord  be  destroyed,  the  tetanus 
ceases.  It  follows  that  the  chief  seat  of  the  action  of  strychnine  lies 
in  the  cord,  but  this  does  not  exclude  the  possibility  that  strychnine 
increases  reflex  excitability  in  the  higher  parts  of  the  central  nervous 
system  as  well  as  in  the  cord. 

That  the  tetanus  is  a  convulsion  of  reflex  origin  and  is  not  caused 
by  direct  stimulation  was  demonstrated  in  1846  by  Hermann  Meyer, 
who  observed  that  after  division  of  all  the  posterior  nerve-roots  in 
frogs,  convulsions  did  not  occur,  while  the  slightest  touch  to  one  of  the 
central  stumps  of  the  roots  caused  most  violent  convulsions.  The  con- 
vulsions cease  and  the  frogs  remain  relaxed  if  the  skin  be  anaesthetized 
by  painting  with  a  solution  of  cocaine,  all  sensory  stimulation  via  the 
nerves  of  touch  being  thus  prevented  (Poulsson).  Moreover,  after  very 
small  doses,  1/50  to  1/100  mg.,  the  simple  avoidance  of  all  stimulation 
or  other  irritation  is  sufficient  to  prevent  the  outbreak  of  convulsions. 
It  is  thus  clear  that  the  central  reflex  mechanism  has  been  rendered 
immensely  more  sensitive  to  the  normal  physiological  stimuli  and  that 
a  direct  stimulation  of  the  motor  ganglia  in  the  anterior  horns  is  not 
produced  by  the  drug. 

This  might  be  concluded  simply  from  the  character  of  the  muscular 
contractions  in  strychnine  convulsions,  for  these  are  not  irregular  or 
fibrillary  twitchings,  but  are  coordinated  simultaneous  contractions  of 
entire  groups  of  muscles.  From  what  is  known  of  the  structure  of  the 
spinal  cord,  such  contractions  can  result  only  with  the  aid  of  receptive 
neurons  which  are  everywhere  connected  with  one  another  by  countless 
anastomoses  and  collaterals  and  which,  when  normally  or  abnormally 
stimulated,  send  their  messages  to  motor  neurons  lying  more  or  less 
distant  from  ftiem,  according  as  the  paths  are  open  for  their  passage 
or  are  more  or  less  obstructed.  On  the  other  hand,  motor  neurons  are 
incapable  of  independently  transmitting  exciting  stimuli  to  each 
other  (Exner1),  for  no  one  has  ever,  by  stimulating  a  motor  nerve, 
succeeded  in  causing  stimulation  in  another  motor  neuron.  These  con- 
ditions and  relationships  are  schematically  illustrated  in  Fig.  2. 
Houghton  and  Muirhead  have  also  brought  experimental  proofs,  based 
on  these  anatomical  facts,  that  strychnine  can  act  only  on  the 
branching  receptive  portions  of  the  reflex  arc. 


STRYCHNINE 


15 


If  a  trace  of  strychnine  is  placed  on  a  limited  portion  of  the  exposed  cord 
of  a  frog  in  which  the  blood  and  lymph  circulation  have  been  abolished,  after 
a  few  seconds  the  following  phenomena  are  observed.  If  a  portion  of  the  skin 
corresponding  in  its  nervous  supply  to  the  poisoned  segment  of  the  cord  be 
touched,  a  convulsion  involving  the  whole  animal  occurs.  If,  however,  any  other 
part  be  touched,  only  the  usual  reflex  movements  result,  and  even  the  muscles 
controlled  by  the  poisoned  segment  react  in  an  entirely  normal  manner.  Inas- 
much as  the  discharge  of  nervous  energy  causing  contractions  of  all  the  muscles 
spreads  only  from  the  poisoned  segment  of  the  cord,  that  is  to  say,  produces 
in  all  the  unpoisoned  motor  cells  of  the  anterior  horn  a  stimulus  resulting  in 
tetanic  contraction  of  the  muscles,  and  as  this  can 
result  only  through  the  agency  of  the  receptive  cell 
mechanisms  and  their  manifold  anastomoses,  it  neces- 
sarily follows  that  these  receptive  cells  are  the  seat 
of  the  abnormally  violent  and  unrestrained  discharge 
of  nervous  energy. 

At  a  later  day,  BaglionP,  in  certain  most  instruc- 
tive experiments,  obtained  entirely  similar  results^, 
iising  an  isolated  nerve  and  spinal  cord  preparation 
connected  only  with  the  hind  legs.  Under  these  con- 
ditions he  found  that  strychnine  acted  only  when  placed 
on  the  dorsal  side  of  the  cord  and  not  when  placed  on 
the  ventral  surface.  An  apparent  contradiction  of 
these  views  is  furnished  by  an  experiment  of  Sherring 
ton.  The  cord  of  a  dog  was  isolated  from  all  external 
impulses  by  cutting  it  across  and  dividing  all  the 
posterior  spinal  nerve-roots.  After  such  preparation, 
strychnine  caused  typical  tetanus,  even  six  weeks  later 
when  all  the  afferent  neurons  had  completely  degener- 
ated (H.  Meyer,  unpublished  experiments).  * 

The  contradiction  is,  however,  only  an  apparent 
one,  for  of  the  mechanisms  which  transmit  stimuli,  only 
those  neurons  coming  from  the  periphery  and  those  com- 
ing from  the  brain  degenerate,  while  the  independent 
"relay  cells"  (Schaltzellen,  Exner's2  a-cells)  with  their 
continuations  remain  unaffected.  These  cells  accordingly 
must  be  able  to  receive  chemical  stimuli  from  the  blood 
or  mechanical  ones  resulting  from  vibration  and  to  co- 
ordinate and  transmit  them  to  the  cells  in  the  anterior 
horns.  These  "  shunting  "  neurons  (Schaltneurone)  may 
be  assumed  to  be  the  seat  of  the  strychnine  action. 


FIG.  2. — Diagrammatic  re- 
presentation of  spinal 
cord.  Blue:  Receptive 
cells  and  tracts.  Red: 
Motor  cells. 


From  consideration  of  these  various  phenomena,  it  may  then  be 
concluded  that  strychnine  affects  the  receptive  neurons  of  the  cord 
in  a  special  fashion  and  with  a  double  effect :  firstly,  in  place  of  normal, 
temporary,  and  sub-maximal  contractions,  only  maximal  and  persisting 
contractions  result  from  reflexes;  and,  secondly,  these  reflex  tonic 
muscular  contractions  are  not  confined  to  that  muscle  group  which  is 
normally  controlled  by  the  stimulated  sensory  neuron,  but  they  involve 
all  the  muscles  of  the  body  and,  as  should  be  especially  noted,  even 
the  antagonistic  muscles. 

THEORY  OF  THE  ACTION  OF  STRYCHNINE. — For  the  better  under- 
standing of  these  phenomena,  one  may  assume  that  certain  inhibitions 
in  the  receptive  organs  of  the  cord  are  removed  by  strychnine.  It  is 
very  probable  that  in  the  sensory  receptive  cells  there  are  certain 
inhibitory  mechanisms,  which  ordinarily  prevent  the  immediate  dis- 
charge of  all  their  stored-up  energy  whenever  they  are  stimulated. 


16     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

For  this  reason,  they  function  only  intermittently,  or,  as  Baglioni- 
expresses  it,  these  sensory  cells  have  a  refractory  period,  in  contra- 
distinction to  the  motor  ganglion  cells  in  the  anterior  horns,  which 
when  stimulated  can  discharge  energy  continually  (Birge,  Bagliom  3). 
This  is  the  reason  why,  under  normal  conditions,  a  tonic  contraction 
of  a  muscle  can  never  be  caused  reflexly, — that  is,  though  the  sensory 
tracts, — but  is  readily  induced  by  direct  stimulation  of  the  motor 
ganglia.  If  this  sensory  mechanism  be  so  affected  by  strychnine  that 
it  loses  this  property  of  becoming  refractory,  it  may  then  discharge 
stimuli  continually  and  excite  tonic  contractions. 

Still  other  inhibitions  of  different  kinds  are  removed  by  strych- 
nine,— for  example,  those  which  normally  prevent  the  stimulation 
of  one  sensory  neuron  from  spreading  at  will  to  other  parts  by  way  of 
secondary  paths.  These  secondary  paths  extend  in  so  many  directions 
and  are  so  branching  that  any  particular  sensory  impulse  from  any 
sensitive  point  could  probably  be  carried  to  all  the  motor  cells  in  the 
central  nervous  system.  As  a  rule,  however,  such  impulse  passes 
only  along  the  shortest  or  most  open  path  which  runs  to  the  physiologi- 
cally more  nearly  related  motor  cells  and  passes  to  all  others  by  way 
of  these  secondary  paths  only  in  imperceptible  and  ineffective  inten- 
sity (Exner3). 

Moreover,  as  a  result  of  Sherrington 's  fundamentally  important 
investigations,  it  has  been  shown  that  normally  the  excitation  of  an 
agonist  (e.g.,  flexor  muscle)  is  regularly  accompanied  by  inhibition 
of  its  antagonist  (e.g.,  the  corresponding  extensor),  and  that,  there- 
fore, normally,  both  cannot  reflexly  be  caused  to  contract.  One  may 
look  upon  this  as  due  to  the  fact  that  between  two  antagonistically 
coordinated  motor  cells  there  is  always  a  reciprocal  inhibitory 
mechanism  which  so  acts,  that  when  a  cell  (m,  Fig.  3)  is  excited,  the 
antagonistic  cell  (mx)  is  automatically  inhibited. 

This  mechanism  is  indicated  diagrammatically  in  the  figure  by 
the  two  arrows  with  the  minus  sign.  Normally,  the  impulse  from  the 
spinal  ganglion  reaches  in  effective  strength  only  the  cell  m,  while 
to  mt  there  comes  only  an  inefficient  impulse,  for  the  path  is  not 
opened,  or  is  obstructed  by  certain  obstacles,  such  as  interposed  cells, 
which  are  indicated  in  the  diagram.  Therefore,  cell  m  is  stimulated, 
while  in  some  way  or  other  mx  is  inhibited.  As  a  result  of  the  action 
of  strychnine,  however,  the  side  path  to  m^  (as  also  all  other  side 
paths)  is  freed  of  all  obstacles  or  inhibitory  influences,  and  permits 
the  passage  of  just  as  much  stimulating  impulse  as  does  the  main 
path  running  to  m.  Thus,  both  cells  m  and  ml  receive  equally  strong 
stimuli,  and  their  reciprocal  intracentral  inhibitory  mechanisms  com- 
pensate each  other,  as  it  were.  As  a  result  agonist  and  antagonist 
both  contract. 

ACTION  IN  HIGHER  ANIMALS. — The  action  of  strychnine  on  reflex 
excitability  is  practically  identical  in  all  vertebrates,  but  in.  the 


STRYCHNINE 


17 


higher  animals  there  is  more  evidence  of  increased  sensitiveness  of 
the  reflexes  in  the  brain,  especially  of  the  reflexes  resulting  from 
stimulation  arising  in  the  more  highly  developed  organs  of  sense. 

In  the  higher  vertebrates  the  susceptibility  to  strychnine  is  much  greater 
than  in  the  frog.  The  lethal  dose  for  the  latter  is  2  mg.  per  kilo.,  while  for 
rabbits,  dogs,  and  cats  it  is  from  0.6-0.75  mg.  per  kilo.  On  the  other  hand, 
birds  are  in  the  highest  degree  insusceptible  to  strychnine  administered  by 
mouth  (Falck), 

After  receiving  an  injection  of  an  effective  dose  of  strychnine,  a 
rabbit  soon  manifests  a  peculiar  uneasiness.  -He- cocks  his  ears,  raises 
his  head£etc>  Soon,  quite  suddenly  and  following  any  sort  of  stimula- 


Fia.  3. — Diagram  of  the  intracentral  inhibitory  mechanism  of  the  spinal  cord. 

tion,  a  tonic  convulsion  occurs,  the  extremities  becoming  stiff  in  a 
position  of  extension,  and  the  body  rigid  in  a  state  of  opisthotonos. 
The  convulsions  may  last  a  minute  or  longer,  and  during  them  the 
tremor  of  the  muscles  may  be  felt. 

As  all  the  respiratory  muscles  take  part  in  the  tonic  contractions, 
respiration  is  prevented  and  the  symptoms  of  asphyxia  appear,  if  the 
convulsion  lasts  long  enough,  but,  as  a  rule,  the  animals  do  not  die 
during  the  convulsion.  More  often,  after  more  or  less  numerous  con- 
vulsions a  condition  of  paralysis  develops.  The  reflex  excitability 
steadily  diminishes,  the  blood-pressure  falls  and  remains  very  low, 
and  the  respirations  become  constantly  weaker  until  they  stop 
entirely. 

In  addition  to  these  characteristic  actions  on  the  reflex  mechanism 
of  the  cord,  in  the  higher  animals  strychnine  exerts  a  similar  exciting 
action  on  the  REFLEX  CENTRES  in  the  CEREBRUM  and  MEDULLA.  The 


18     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

blood-pressure  rises  during  the  convulsions  and  the  pulse  becomes 
slow,  even  when  asphyxia  is  prevented  by  artificial  respiration.  Also 
when  the  convulsions  are  prevented  by  curare,  there  are  periodic 
recurrences  of  the  rise  in  blood-pressure  and  of  slowing  of  the  pulse 
(8.  Mayer)  for  which  the  increased  excitability  of  the  vasomotor  and 
vagus  centres  is  responsible.  A  similar  action  on  the  RESPIRATORY 
CENTRE  also  occurs,  for  it  may  be  shown  experimentally  that  after 
the  excitability  of  the  respiratory  centre  has  been  markedly  depressed 
by  such  a  drug  as  morphine,  strychnine  in  doses  which  are  not  large 
enough  to  cause  convulsions  will  bring  about  a  marked  increase  in 
the  excitability  of  this  centre  (Biberfeld) . 

The  action  of  strychnine  on  the  different  SPECIAL  SENSES  is  of  con- 
siderable therapeutic  importance.  Touch,  smell,  and  taste  all  become 
more  acute,  and  the  sensitiveness  of  the  visual  organs  is  improved  so 
that  the  field  of  vision  is  enlarged  and  the  ability  to  distinguish  colors 
is  increased.  Filehne  has  shown  that  these  effects,  except  those  on 
vision,  are  the  results  of  an  action  on  the  central  sensory  tracts  in 
the  cerebrum.  In  the  eye  the  drug  acts  directly  on  the  retina,  which, 
as  is  well  known,  may  be  looked  upon  as  a  portion  of  the  cerebrum. 
Inasmuch  as  this  increase  in  the  sharpness  of  the  senses  results  from 
an  action  of  strychnine  on  the  sensory  centres  in  the  brain,  the  in- 
creased sensibility  of  the  senses  appears  entirely  analogous  with  the 
increased  excitability  of  the  sensory  organs  in  the  cord. 

PARALYTIC  ACTION  OF  STRYCHNINE. — Strychnine,  however,  exerts 
still  other  actions  on  the  nervous  system.  Mammals,  as  well  as  frogs, 
die  in  a  state  of  paralysis  which  follows  the  convulsions.  This  has 
often  been  explained  as  due  to  an  exhaustion  of  the  nervous  system 
as  a  result  of  the  convulsions.  While  it  is  a  fact  that  an  increased 
tendency  to  exhaustion  goes  hand  in  hand  with  the  increased  excita- 
bility of  the  reflex  organs,  for  the  unchecked  discharge  of  impulses 
readily  leads  to  an  exhaustion  of  the  energy  in  the  receptive  organs 
which  have  no  time  to  rest  or  to  form  anew  those  substances  consumed 
by  their  discharge  of  energy,  still  the  exhaustion  of  the  cord  resulting 
from  the  convulsions  in  one  way  explains  the  rapid  paralysis  occurring 
in  frogs  after  large  doses  of  strychnine.  Neither  does  it  explain  the 
fact  that  in  mammals  death  results  from  respiratory  and  vasomotor 
paralysis,  which  may  occur  after  only  a  few  convulsions.  These 
phenomena  result  rather  from  another  later  action  of  strychnine,  a 
paralyzing  one,  which  is  more  in  evidence,  as  compared  with  the 
convulsant  action,  the  larger  the  amounts  of  the  poison  absorbed. 

In  such  case  a  general  paralysis  develops  after  tetanus  of  short 
duration.  In  frogs  in  which  this  paralysis  is  not  fatal,  a  tetanus 


STRYCHNINE  19 

lasting  for  days  may  be  observed  after  the  paralysis  has  passed  off. 
This  paralysis  also  has  nothing  to  do  with  that  depression  of  the 
heart  which  occurs  after  large  toxic  doses  of  strychnine  (Igersheimer). 
It  is  the  final  cause  of  death  in  cases  when  very  large  amounts  of  the 
poison  have  been  taken  (Poulsson). 

After  large  doses  of  strychnine  a  "curare"  action  occurs  in  the 
frog,  which  is  much  better  developed  in  the  Rana  esculenta  than  in 
the  R.  temporaria. 

It  is  a  noteworthy  fact  that  at  a  time  when  the  reflex  excitability 
from  tactile  skin  irritation  is  highly  exaggerated,  chemical  irritation 
of  the  skin  (by  acetic  acid)  and  other  painful  stimuli  (by  cutting) 
produce  no  effect.  Moreover,  irritation  of  the  viscera,  which  in 
normal  frogs  causes  defective  movements,  has  no  effect  in  strych- 
ninized  ones.  It  is,  therefore,  apparent  that  the  different  receptive 
systems  in  the  spinal  cord  are  variously  affected  by  this  drug.  The 
perception  of  a  painful  stimuli  is  from  the  start  diminished  as  a  result 
of  a  central  depressing  action.  Only  for  the  stimuli  through  the  ordi- 
nary senses  does  the  nervous  system  become  over-excitable  (T.  Sano). 

TOXICOLOGY. — Strychnine  poisoning  in  man  occurs  usually  as  a 
result  of  taking  the  poison  by  mistake  or  as  the  result  of  exceeding 
the  permissible  medicinal  dose.  The  premonitory  symptoms  are  feel- 
ings of  drawing  and  stiffness  in  certain  muscles,  hypersusceptibility  to 
sensory  impressions,  restlessness,  and  trembling.  After  larger  doses 
(more  than  0.03  gm.)  exaggerated  reflex  excitability  and  a  marked 
feeling  of  anxiety  develop  and  suddenly  the  attacks  of  general  tetanic 
convulsions  start.  The  convulsions  may  last  from  several  seconds  to 
two  minutes,  and,  as  during  them  respiration  ceases,  death  may  result 
from  asphyxia.  In  the  intervals  between  the  convulsions  the  con- 
sciousness is  maintained,  but  during  the  convulsions  the  increasing 
asphyxia  beclouds  it.  Usually  after  three  or  four  severe  convulsions 
death  results  from  exhaustion  of  the  nervous  system  (Denys}.  The 
mean  lethal  dose  for  an  adult  is  from  0.1-0.12  gm. 

In  the  TREATMENT  OP  STRYCHNINE  POISONING  the  first  aim  is  to 
prevent  the  occurrence  or  to  lessen  the  violence  of  the  convulsions, 
which  in  themselves  jeopardize  life.  This  may  be  accomplished  either 
by  quieting  the  hyperexcitable  centres  by  the  administration  of 
narcotics  or  by  interfering  with  the  passage  of  the  abnormally  violent 
motor  stimuli,  which  may  be  done  by  depressing  the  motor  nerve- 
endings  with  curare.  Theoretically  the  treatment  with  curare  should 
be  the  more  efficient  treatment  for  strychnine  poisoning,  for,  as  strych- 
nine itself  exerts  a  paralyzing  action  on  the  nervous  centres,  the  ad- 
ministration of  narcotic  drugs  increases  the  danger  of  the  develop- 
ment of  such  central  paralysis.  However,  as  stated  in  the  discussion 


20         PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

of  curare,  it  is  difficult  to  determine  the  dosage  of  this  drug  exactly 
enough  to  secure  cessation  of  the  convulsions  without  also  stopping 
the  respiration. 

If  the  convulsions  have  not  already  started,  chloral  should  be  given 
by  mouth  or  by  rectum,  or,  if  nothing  else  is  at  hand,  alcohol  in  one 
form  or  another.  All  noises,  draughts,  or  sensory  stimuli  are  to  be 
avoided,  and  finally,  by  apomorphine  or  by  lavage,  any  unabsorbed 
poison  should  be  removed  from  the  stomach.  [Even  although  the  con- 
vulsions have  not  yet  started,  the  administration  of  apomorphine 
and  the  resulting  vomiting,  or  the  use  of  the  stomach-tube,  is  extremely 
liable  to  start  up  the  convulsions  in  an  unansesthetized  patient. — TR.] 
If  the  convulsions  have  already  started,  chloroform  anaesthesia  should 
at  once  be  induced  and  the  stomach  emptied  by  lavage.  As  the 
chloroform  anaesthesia  passes  off,  chloral  hydrate  should  be  given  by 
rectum  and  measures  taken  to  stimulate  diuresis,  in  order  that  the 
strychnine  may  be  excreted  while  the  patient  is  sleeping  under  the 
influence  of  chloral. 

In  animal  experiments  artificial  respiration  may  bring  about  a 
cessation  of  the  convulsions  caused  by  strychnine.  The  breathing  of 
pure  oxygen  also  moderates  or  prevents  the  occurrence  of  the  con- 
vulsions, while  an  insufficient  oxygen  supply  augments  their  violence 
(Osterwald). 

THERAPEUTIC  USES. — Among  the  therapeutic  indications  for  strych- 
nine is  its  employment  in  amblyopias  and  amauroses  without  ana- 
tomical change  or  in  incipient  optic  atrophy,  in  which  conditions  its 
curative  or  helpful  action  has  been  certainly  demonstrated.  More- 
over, in  cases  of  impaired  hearing  of  central  origin,  improvement  has 
been  claimed  from  its  use  in  dosage  up  to  0.01  gm.  per  dose  ( !)  and 
0.02  gm.  per  diem  (!)  of  strychnine  nitrate,  subcutaneously  injected. 
Its  use  in  motor  paralysis  is  recommended  from  many  sides. 
Naunyn,  among  others,  reports  good  results  in  pareses,  but  never 
in  complete  paralysis,  from  the  daily  injection  of  0.01  gm.  in 
series  of  10-12  injections,  with  6-8  days'  intervals  intervening.  It 
would  thus  appear  that  this  drug  favorably  influences  the  re-establish- 
ment of  motor  functions  only  when  the  interruption  of  the  motor  tract 
is  not  a  complete  one.  Strychnine  is  also  used  in  cases  of  paralysis 
or  weakness  of  the  sphincters  and  in  nocturnal  enuresis. 

In  atony  of  the  alimentary  canal  the  effect  of  strychnine  is  uncer- 
tain. For  this  indication  it  may  be  used  in  the  form  of  the  extract 
1-5  eg.  (!)  per  dose  up  to  0.1  gm.  ( !)  per  diem.  The  employment  of 
the  tincture  in  various  affections  of  the  stomach  and  intestines  rests 
probably  upon  its  action  as  a  bitter. 


STRYCHNINE  21 

The  employment  of  STRYCHNINE  as  an  ANTIDOTE  in  NARCOTIC  POIS- 
ONINGS, especially  in  poisoning  with  chloral  hydrate,  alcohol,  centrally 
depressing  snake-poisons,  etc.,  rests  on  a  better  physiological  foundation 
than  the  above-mentioned  therapeutic  uses.  In  other  countries  strych- 
nine is  used  much  oftener  for  such  indications  than  in  Germany, 
where  the  preference  is  given  to  the  harmless  caffeine.  As  the 
excretion  of  strychnine  by  the  kidney  takes  place  extremely  slowly 
(Ipsen),  it  can  accumulate  in  the  body  when  administered  for  a 
considerable  period. 

[That  strychnine  is  of  value  as  a  stimulant  in  various  conditions 
of  depression  of  the  central  nervous  system,  especially  in  infectious 
disease,  is  firmly  believed  by  many  physicians,  of  whom  the  translator 
is  one.  That  its  value  is  often  over-estimated  is  probably  true,  but 
the  weight  of  clinical  evidence  certainly  is  in  favor  of  its  usefulness 
in  such  indications.  Nothing,  however,  can  be  expected  from  small 
doses,  such  as  1.0  mg.  3  to  6  times  a  day,  which  are  the  usual  doses 
given.  Doses  three  or  more  times  as  large  are,  as  a  rule,  the  only  ones 
capable  of  producing  real  benefit.  Naturally,  when  such  larger  doses 
are  given,  the  patient  should  be  carefully  watched,  and  at  the  first 
sign  of  exaggerated  reflex  excitability  the  drug  should  be  diminished 
or  stopped.  In  this  connection  the  translator  would  call  attention  to 
the  antagonistic  effects  of  alcohol  and  strychnine,  which  would  appear 
to  him  to  indicate  that  it  is  irrational,  at  least  in  respect  to  the  effects 
on  the  central  nervous  system,  to  give  to  a  patient  large  doses  of  both 
of  these  drugs. — TR.] 

BRUCINE,  which  occurs  together  with  strychnine  in  nux  vomica, 
is  chemically  closely  related  to  it,  being  probably  dimethyloxystrych- 
nine  (J.  Tafel),  and  its  physiological  action  is  similar  to  that  of 
strychnine,  but  much  weaker. 

BIBLIOGRAPHY 

^aglioni:    Zeitschr.  f.  allg.  Phys.,  1909,  vol.  9,  p.  1. 

"Baglioni:    Zeitschr.  f.  allg.  Phys.,  1904,  vol.  4,  p.  113. 

"Baglioni:   Zeitschr.  f.  allg.  Phys.,  1909,  vol.  10,  p.  87. 

Biberfeld:   Pfliiger's  Arch.  f.  d.  ges.  Physiol.,  1904,  vol.  103,  p.  266. 

Birge:   Dubois'  Arch.,   1882,  p.  481. 

Bongers,  P.:   Arch.  f.  Anat.  u.  Phys.,  1884,  p.  331. 

Denys:  Arch.  f.  exp.  Path.  u.  Pharm.,  1885,  vol.  20. 

1Exner:    Entwurf  zu  einer  Erklarung  d.  psychischen  Erscheinungen,  1894,  p.  59. 

2  Exner :    Loe.  cit.,  pp.  88,  92  ff. 

*  Exner:    Loc.  cit.,  pp.  58,  59. 

Falck:   Zentralblatt  f.  d.  med.  Wissenschaften,  1899,  No.  29. 

Filehne:   Pfluger's  Arch.,   1901,   83,  with   literature,  p.  369. 

Harnack,  E.:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  34,  p.  156. 

Houghton  and  Muirhead:   Med.  News,  1895. 

Igersheimer:   Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  54. 

Ipsen:   Vierteljahrschrift  f.  gerichtl.  Medizin,  1892,  vol.  4,  p.  15. 

Kolliker:  Virchow's  Arch.,   1856,  vol.   10,   p.  239. 

Mayer,  S.:    Ber.  d.  kais.  Akad.  d.  Wissensch.  in  Wien,  1872,  vol.  64,  Part  II, 

p.  657. 
Meyer,  H. :  Zeitschr.  f.  rationelle  Medizin,  1846,  vol.  5,  p.  257. 


Miiller,  Johann:   Handbuch  d.  Phys.  d.  Menschen,  1844,  p.  49. 

Naunyn:     Ueber   subcutane  Strychnineinspritzungen,   Ges.  Abhandlungen,    1909, 

vol.  2,  p.  790. 

Osterwald:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  44,  p.  451. 
Poulsson,  E.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1889,  vol.  26,  p.  22  ff. 
Sano,  T.:  Pfliiger's  Arch.,  1908,  vol.  124. 

Sherrington:  Phil.  Transact.  Roy.  Soc.,  1898,  vol.  190,  p.  160. 
Tafel,  Jul.:   Liebig's  Annalen,   1898,  vol.  304,  p.  26. 

GENERAL  CHARACTERISTICS  OF  ALKALOIDS 

As  has  been  mentioned,  strychnine  is  a  typical  alkaloid,  and,  as 
many  of  our  most  important  drugs  belong  in  this  group,  a  brief 
description  of  their  general  characteristics  will  be  advantageous  at 
this  time. 

The  alkaloids  are  nitrogenous  bases,  chiefly  of  vegetable  origin. 
Commonly,  however,  this  term  is  applied  only  to  those  vegetable  bases 
which  exert  powerful  physiological  actions,  although  it  is  also  applied 
to  certain  bases  formed  by  the  decomposition  of  animal  tissues,  the 
so-called  ptomaines,  or  cadaveric  alkaloids. 

Most  alkaloids  contain  C,  N,  H,  and  O,  but  a  few  contain  no  0. 
In  general  they  may  be  considered  to  be  substituted  ammonias  or 
ammonium  bases,  the  nitrogen  in  most  of  them  entering  into  the 
formation  of  such  closed  carbon  rings  as  those  of  pyrrhol,  pyridine, 
quinolin,  etc. 

As  a  result  of  their  basic  character  they,  like  ammonia,  readily 
form  salts  with  acids.  These  are  broken  up  by  ammonia,  fixed  alka- 
lies, and  other  bases,  in  accordance  with  their  mass  action  and  their 
basicity.  In  this  way  the  insoluble  alkaloids  may  be  precipitated  from 
aqueous  solutions  of  their  salts. 

In  contradistinction  to  the  free  alkaloids,  these  salts  are,  as  a  rule, 
soluble  in  water  and  in  alcohol,  but  are  insoluble  in  benzene,  ether, 
chloroform,  and  amyl  alcohol,  in  which  the  free  alkaloids  are  more  or 
less  soluble.  The  usual  methods  of  isolating  alkaloids  are  based  on 
these  solubilities  and  insolubilities. 

After  isolation  the  alkaloids  are  identified  by  various  methods, 
among  which  only  the  color-reactions  and  physiological  tests  need 
be  mentioned  here.  As  the  color-reactions  often  are  ambiguous  unless 
the  alkaloid  is  absolutely  uncontaminated  by  other  substances,  the 
physiological  tests  are  often  more  positive  and  more  definite  than  the 
tests  based  on  color-reactions.  This  is  notably  the  case  with  strych- 
nine (Ranke). 

Tannic,  phosphomolybdic,  phosphotungstic,  and  picric  acids  form 
with  most  alkaloids,  even  when  highly  diluted,  salts  which  are  very 
insoluble  in  water  and  which  consequently  are  precipitated.  The 
chlorides  of  platinum  and  gold  and  the  chlorides  and  iodides  of  mer- 
cury, bismuth,  and  zinc  form  with  the  chlorides  of  most  alkaloids 
very  insoluble  double  salts.  These  reagents  may  therefore  be  used 
to  determine  the  presence  of  alkaloids. 


CONVULSANTS  23 

CONVULSANTS 

Besides  the  toxic  excitation  caused  by  strychnine,  the  typical  con- 
vnlsant,  there  are  other  types  of  toxic  excitation  of  the  central  nervous 
system  which  may  excite  convulsions,  which,  however,  are  not  pre- 
cipitated by  sensory  stimuli,  and  hence  are  not  of  a  reflex  character. 
Such  convulsions  differ  from  those  produced  by  strychnine  in  not 
being  characterized  by  a  simultaneous  contraction  of  all  the  muscles 
in  the  body  (including  the  antagonists),  for  in  them  only  certain 
groups  of  muscles  contract.  As  previously  stated,  in  strychnine 
convulsions  all  the  muscles,  both  agonists  and  antagonists,  contract 
simultaneously,  a  tetanic  or  tonic  convulsion  resulting.  This  simul- 
taneous contraction  of  all  the  muscles  finds  its  explanation,  as  already 
stated,  in  the  unhindered  spreading  of  the  sensory  stimulus  over  all 
the  afferent  paths  and  bypaths,  this  resulting  in  an  equally  simul- 
taneous excitation  of  all  the  motor  centres,  even  the  antagonistic  ones. 
On  the  other  hand,  certain  other  convulsant  poisons,  without  inter- 
fering with  the  inhibition  of  the  antagonists,  cause  involuntary  muscu- 
lar movements  similar  to  those  of  orderly  normal  motions.  Such  con- 
vulsions are  known  as  clonic  convulsions,  and  it  is  characteristic  of 
them  that  their  occurrence  is  apparently  spontaneous  although  in  real- 
ity they  are  caused  by  summation  of  internal  stimuli.  Like  epileptic 
attacks,  after  a  short  period  they  cease  for  a  time,  and  therefore  are 
described  as  being  of  a  periodic  or  epileptiform  type. 

In  contradistinction  to  the  tonic  convulsions  which  are  of  spinal 
causation,  these  epileptiform  convulsions  are  excited  by  conditions 
arising  in  the  higher  centres  normally  controlling  voluntary  move- 
ments, which  in  different  species  of  animals  are  situated  in  different 
parts  of  the  central  nervous  system. 

For  this  reason  there  has  arisen  much  confusion  in  the  statements  about 
the  seat  of  action  of  the  so-called  convulsants.  Prevost  and  Batelli,  by  stimulat- 
ing various  portions  of  the  central  nervous  system  with  a  powerful  alternating 
current,  endeavored  to  determine  the  parts  of  the  central  nervous  system  from 
which  clonic,  and  those  from  which  tonic  convulsions  could  be  excited.  In 
full-grown  dogs  and  cats,  these  authors  found  that  clonic  convulsions  resulted 
only  when  the  cortical  motor  regions  were  stimulated,  while  stimulation  of  the 
centres  lower  down  caused  tonic  convulsions.  On  the  other  hand,  stimulation 
of  the  cerebral  cortex  in  rabbits,  guinea-pigs,  and  new-born  dogs  and  cats  was 
not  followed  by  clonic  convulsions,  but  these  did  occur  when  the  medulla  of 
these  animals  was  stimulated.  Stimulation  of  the  spinal  cord  may  cause  clonic  con- 
vulsions in  frogs,  but  only  tonic  contractions  in  the  higher  animals  (Samaya). 

It  would,  therefore,  appear  that,  in  the  higher  animals,  EPILEPTI- 
FORM CONVULSIONS  OF  TOXIC  ORIGIN  ARE  DUE  CHIEFLY  TO  THE  ACTIONS 
OF  VARIOUS  POISONS  ON  THE  CEREBRAL  CORTEX.  It  IS,  however,  not 

impossible  that  such  poisons  may  also  act  on  the  subcortical  centres. 

By  certain  experiments  ( Luchsinger)  in  which  transverse  section  of  the 
central  nervous  system  was  performed  at  different  levels,  it  has  been  demon- 
strated that  picrotoxin,  a  typical  convulsant,  causes  convulsions  not  only  by 
its  action  on  some  higher  portion  of  the  central  nervous  system  but  also  by  its 
action  on  centres  in  the  cord.  On  the  other  hand,  there  are  other  convulsant 


24      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

poisons  whose  seat  of  action  is  sharply  limited;  for  example,  the  esters  of 
morphine-glycocholic  acid,  which  cause  violent  convulsions.  By  similar  ex- 
periments these  convulsions  have  been  shown  to  be  due  to  an  action  on  certain 
centres  in  the  pons,  the  other  portions  of  the  central  nervous  system  not  being 
involved  ( Barnes ) . 

The  large  number  of  the  regions,  from  which  clonic  convulsions 
may  be  excited,  sufficiently  explains  our  incomplete  knowledge  of  the 
place  and  manner  of  their  causation. 

CAMPHOR. — Among  the  many  substances  which  may  cause  epilepti- 
form  convulsions,  camphor  should  be  especially  mentioned.  In  warm- 
blooded animals  large  doses  of  this  drug  cause  convulsions  with  clonic 
movements  of  the  extremities,  trismus,  and  tonic  contraction  of  the 
facial  muscles,  which,  in  their  periodic  character  and  slight  danger 
to  life,  are  typically  epileptif orm,  and  are  rarely  followed  by  paralysis 
or  even  marked  weakness.  The  therapeutic  action  of  camphor  on  the 
central  nervous  system  depends  on  the  fact  that  doses,  too  small  to 
cause  convulsions,  stimulate  certain  vitally  important  cerebral  and 
medullary  functions.  Other  convulsants — e.g.,  PICROTOXIN  and  coria- 
myrtin  (from  Coriaria  myrtifolia) — produce  similar  effects  (Koppen). 

A  stimulation  of  the  CONVULSION  centres  may  also  occur  AS  A 
TOXIC  SIDE-ACTION  of  a  number  of  other  much-used  drugs.  For  ex- 
ample, in  even  slight  ATROPINE  poisoning  a  certain  degree  of  motor 
unrest  with  involuntary  movements  of  the  hands  and  fingers  occurs, 
while  in  severe  poisoning  there  occur  outbreaks  of  clonic  convulsive 
movements  of  the  extremities,  trismus,  and  rolling  and  twisting 
movements,  which  may  continue  to  recur  for  hours  or  for  days.  In 
COCAINE  poisoning,  too,  both  epileptiform  and  tonic  convulsions  may 
occur.  SANTONIN,  so  widely  used  as  a  vermifuge,  is  also  a  typical 
convulsant  and  has  often  been  responsible  for  poisoning  in  which 
epileptiform  convulsions  occur. 

BIBLIOGRAPHY 

Barnes:    Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46,  p.  68. 
Gottlieb:   Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30. 
Koppen:    Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  29,  p.  327. 
Luchsinger:   Pfliiger's  Arch.,   1878,  vol.   16,  p.  532. 

Prevost  u.  Batelli:  Travaux  du  laborat.  de  physiol.  de  Geneve,  1894,  vol.  5. 
Ranke:  Virchow's  Arch.,  1879,  vol.  75. 
Samaya:    Trav.  du  lab.  de  physiol.  de  Geneve,  1903,  vol.  4. 

CEREBRAL   STIMULANTS 

Wherever  convulsions  occur  as  toxic  side  effects,  this  will  be 
mentioned  in  the  general  discussion  of  the  drug.  In  this  connection 
it  should  be  particularly  noted  that  the  higher  psychic  portions  of 
the  cerebrum,  the  centres  of  conscious  perception  and  for  voluntary 
movement,  are  capable  of  a  stimulation  or  of  an  exaltation  of  their 
excitability  similar  to  that  which  the  convulsive  centres  manifest  in 
more  advanced  poisoning.  The  earlier  stages  of  such  actions  may  be 
utilized  therapeutically  to  stimulate  cerebral  functions  when  they 


CEREBRAL  STIMULANTS  25 

are  depressed.  The  discussion  of  the  action  of  strychnine  on  the 
central  perception  of  sensory  stimulation  has  made  it  clear  that 
certain  drugs  can  produce  such  an  exaltation  of  the  excitability  of 
such  cortical  centres.  In  an  analogous  fashion,  stimulating  drugs  may 
bring  about  an  improvement  of  the  functions  of  those  other  centres 
on  the  activity  of  which  consciousness  depends.  At  any  rate,  there 
is  at  the  present  time  no  conclusive  evidence  which  forces  us  to  believe 
that  the  symptoms  of  cerebral  stimulation  are  always  only  a  secondary 
result  of  the  depression  of  higher  psychic  centres,  the  inhibitory  ones 
in  particular. 

The  clearest  evidence  that  a  direct  stimulation  of  the  cerebral  func- 
tions may  occur  is  found  in  the  fact  that  depression  of  the  cerebrum 
may  be  combated  by  stimulating  substances.  In  animals  conditions 
of  cerebral  narcosis,  such  as  are  produced  by  alcohol,  paraldehyde,  or 
chloral,  may  be  interrupted  or  overcome  by  the  administration  of 
stimulating  drugs,  even  after  consciousness,  voluntary  movements, 
and  perception  of  pain  are  abolished  and  most  of  the  reflexes,  includ- 
ing the  corneal,  are  markedly  depressed. 

In  dogs,  Bins  demonstrated  the  antagonistic  action  of  caffeine  and  alcohol, 
and  1/osso,  by  injections  of  0.01-0.02  gm.  of  cocaine  hydrochlorate,  was  able  to 
awaken  dogs  from  the  deep  sleep  produced  by  chloral.  Schmiedeberg  found  that 
"  rabbits,  narcotized  by  paraldehyde  until  consciousness  was  completely  abolished, 
could  be  so  thoroughly  awakened  by  injection  of  ^  to  1  mg.  of  picrotoxin,  that 
they  moved  about  in  quite  a  lively  fashion."  Koppen  succeeded  in  doing  the 
same  with  coriamyrtin  injected  into  rabbits  narcotized  by  chloral,  and  Gottlieb. 
after  injecting  camphor  into  rabbits  deeply  narcotized  by  paraldehyde,  observed 
the  return  of  the  reflexes  (including  the  corneal)  which  had  been  abolished,  the 
animals  waking  up  and  moving  about  voluntarily.  This  last-cited  observation 
illustrates  well  the  REVIVING  ACTION  OF  CAMPHOR  on  the  sensorium,  which  is  at 
times  observed  even  after  its  administration  to  patients  in  extremis. 

THERAPEUTIC  INDICATIONS. — The  indications  for  the  administration 
of  these  STIMULANTS  OF  THE  CENTRAL  NERVOUS  SYSTEM  are  found  in  all 
acute  conditions  of  depression  which  are  characterized  by  a  failure 
of  such  vital  functions  as  those  of  the  respiratory  and  vasomotor 
centres.  Such  a  condition  is  that  of  the  so-called  collapse.  The 
stimulating  effects  of  CAMPHOR,  CAFFEINE,  ATROPINE,  and  other  drugs, 
indicated  in  collapse,  are  chiefly  due  to  their  action  on  the  circulation 
and  respiration,  and  therefore  this  will  be  more  fully  discussed  in  the 
sections  dealing  with  the  pharmacology  of  those  functions.  However, 
when  they  are  employed,  they  also  produce  a  stimulation  of  the  cere- 
bral functions  whenever  it  is  still  possible  to  produce  any  affects 
opposing  the  depression  of  the  central  nervous  system. 

In  addition  to  their  therapeutic  actions,  the  drugs  of  this  class 
are  of  importance  on  account  of  their  extensive  consumption  in  various 
BEVERAGES.  Especially  is  this  the  case  with  caffeine,  for  even  the 
small  amounts  of  the  drug,  which  are  present  in  tea,  coffee,  and  some 
other  commonly  used  beverages,  produce  readily  recognizable  effects 


26     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

on  the  normal  central  nervous  system.  In  animals  the  toxic  action 
of  caffeine  manifests  itself  by  an  exaggeration  of  the  reflexes,  especially 
the  spinal  ones,  which  is  entirely  analogous  to  that  produced  by  strych- 
nine. In  man  the  toxic  action  manifests  itself  chiefly  by  the  symptoms 
of  its  cerebral  effects,  restlessness  and  great  excitement  (Curschmann) . 
In  susceptible  individuals,  even  small  amounts  produce  the  first  stages 
of  cerebral  excitement  with  an  increased  reflex  excitability.  This  is 
the  reason  why  many  individuals  are  unable  to  fall  asleep  as  usual 
after  drinking  such  beverages  as  tea  and  coffee.  Krdpelin's  delicate 
psychophysical  analysis  of  the  effects  of  tea  shows  that  these  are  due 
almost  entirely  to  the  caffeine  contained  in  it.  Making  use  of  methods 
permitting  of  exact  measurements,  he  found  that  tea  improves  the 
perception  of  external  stimuli  and  also  the  association  of  ideas.  This 
confirms  the  every-day  experience  that  caffeine  favors  the  performance 
of  certain  cerebral  functions  and  opposes  the  depressing  effects  of 
alcohol  and  of  mental  fatigue. 

CAFFEINE  is  a  drug  whose  action  is  almost  purely  stimulating. 
Unlike  strychnine,  it  does  not,  even  in  large  doses,  cause  a  later  stage 
of  depression.  However,  a  certain  amount  of  confusion  of  the  cere- 
bral functions  does  result  from  poisonous  doses,  this  indicating  that 
such  doses  do  exert  a  certain  degree  of  depressing  action  of  some  of 
the  brain  centres.  Of  the  other  cerebral  stimulants  which  are  of 
practical  importance,  camphor  is  one  producing  similar  effects  with 
but  slight  late  depressing  action,  while  most  of  the  other  convulsants, 
when  given  in  large  doses,  cause  not  only  stimulation  of  certain  func- 
tions of  the  brain  but  also  depression  of  others,  or  else  a  stimulation 
quickly  followed  by  depression.  This  is  the  case,  for  instance,  with 
cocaine,  so  that  in  poisoning  caused  by  it  extreme  mental  excitement 
and  motor  restlessness  are  accompanied  by  clouding  of  the  conscious- 
ness, while  a  marked  depression  of  the  central  nervous  system  suc- 
ceeds the  stage  of  excitation.  With  this  drug,  even  in  the  early  stages 
of  the  action  on  the  central  nervous  system,  there  is  clear  evidence 
of  interference  with  some  of  the  higher  brain  functions,  so  the  con- 
dition may  be  spoken  of  as  a  cocaine  "jag"  (Rausch).  Only  after 
very  small  doses  is  its  action  an  almost  exclusively  stimulating  one. 
Such  are  the  doses  taken  by  the  natives  of  South  Africa  when  chewing 
coca  leaves,  and  it  is  this  stimulating  action  on  the  cerebrum  which 
accounts  for  this  custom. 

BIBLIOGRAPHY 

Binz:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  9,  p.  31. 

Curschmann:    Deutsche  Klinik,  1873,  p.  377. 

Gottlieb:    Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30,  p.  21,  exp.  p.  39. 

Kelp:   Cited  from  Binz,  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  9,  p.  41. 

Koppen:    Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  29,  p.  327,  exp.  p.  343. 

Krapelin:    Ueber  die  Beeinflussung  einfacher  psychischer  Vorgange  durch  einige 

Arzneimittel,  Jena,  1892,  p.  216. 

Mosso:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  23,  p.  205. 
Schmiedeberg:    Grundriss  der  Pharmakologie,  Leipzig,  1906,  p.  264. 


ATROPINE,  SCOPOLAMINE  27 

DEPRESSION 


ATROPINE. — The  symptoms  produced  by  atropine  are  typical  of 
such  a  combination  of  stimulation  and  depression  occurring  side  by 
side  in  the  cerebrum.  A  peculiar  psychic  confusion,  with  hallucina- 
tions and  deception  of  the  senses,  accompanies  even  slight  grades  of 
poisoning  by  this  drug,  while  severely  poisoned  individuals  lose  con- 
sciousness during  the  stage  of  delirium  and  convulsions.  After  the 
stage  of  excitement  passes  off,  they  pass  into  a  half-ct)maTose  state, 
and  in  fatal  cases  death  ensues  from  the  paralysis  which  then  develops. 
With  a  group  of  alkaloids  closely  related  to  atropine,  the  central 
action  causes,  after  only  a  short  stage  of  excitement,  a  depression  of  j 
the  cerebral  functions. 

SCOPOLAMINE. — This  is  most  pronounced  in  the  case  of  scopolamine 
(identical  with  hyoscine),  which  is  widely  used  as  a  sedative  and  hyp- 
notic and  which  in  its  peripheral  actions  closely  resembles  atropine. 
Its  therapeutic  usefulness  results  from  its  actions  on  the  central  ner- 
vous system,  which  differ  from  those  of  atropine  in  that  with  scopo- 
lamine a  primary  depression  of  certain  cerebral  centres  is  more 
prominent  than  is  the  case  with  atropine.  Scopolamine  may,  there- 
fore, be  used  to  induce  sleep  or  at  least  to  produce  a  sedative  effect  in 
cases  of  most  pronounced  excitement,  where  other  hypnotics  (even 
opium)  are  ineffective. 

Scopolamine  is  a  Isevorotary  alkaloid  with  the  formulae  C1TH21NO4,  which 
occurs  in  the  various  solanaceae.  First  discovered  in  Scopolia  atropoides,  but 
also  present  with  hyoscyamine  in  Hyoscyamus  niger  and  Duboisia  myropoides, 
and  in  small  amounts  also  in  Atropa  belladonna  and  other  related  plants. 
Chemically  it  resembles  atropine  closely.  Scopolamine  was  formerly  named 
hyoscine  and  was  chiefly  prepared  from  Hyoscyamus  niger,  but  later  investiga- 
tions have  established  the  identity  of  hyoscine  and  scopolamine  (E.  Schmidt). 

Scopolamine  resembles  atropine  closely  in  its  peripheral  effects  on 
the  pupils,  secretions,  etc.  Its  therapeutic  importance  is,  however, 
due  to  its  central  actions,  which  are  distinguished  from  those  of  atro- 
pine by  a  much  more  prominent  primary  depression  of  certain 
cerebral  centres.  For  a  long  time  it  has  been  known  that  the  extract 
made  from  henbane  acted  as  a  sedative, — that  is,  in  a  different  fashion 
from  the  atropine  and  hyoscamine  contained  in  it.  Impure  prepara- 
tions of  hyoscamine,  which  probably  contain  scopolamine,  have  often 
been  used  with  varying  success  as  a  means  of  quieting  insane  patients. 
Pure  hyoscine,  first  isolated  by  Ladenburg,  was  a  third  alkaloid 
obtained  from  hyoscyamus,  and  later,  when  proved  to  be  identical 
with  scopolamine,  was  introduced  into  therapeutics  by  Gnauck  and 
others. 


28      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

It  has  been  experimentally  demonstrated  that  scopolamine  has  scarcely  any 
narcotic  action  in  rabbits,  but  shortly  after  injection  of  an  effective  dose  dogs 
fall  more  or  less  deeply  asleep.  Before  going  to  sleep,  they  manifest  a  distinct 
restlessness,  evidently  due  to  hallucinations  and  illusions,  which  is  accompanied 
.by  uncertain  gait  and  staggering,  briefly  by  a  tipsy  condition,  which  precedes 
the  stage  of  fatigue  and  sleepiness. 

Man  is,  however,  more  susceptible  to  the  central  action  of  scopola- 
mine, and  doses  of  %-!%  m£-  are  usually  enough  to  produce  the 
required  sedative  effect.  [Few  would  care  to  give  l1/^.  mg.  (V40  g1*-)  ; 
at  any  rate,  as  a  first  dose. — TR.]  Mydriasis  and  paralysis  of  the 
accommodation  and  dryness  in  the  mouth  and  throat  are  accompany- 
ing side  effects.  The  drug  is  usually  used  in  the  form  of  the  hydro- 
bromide  and  is  best  administered  subcutaneously. 

Although  one  speaks  of  SCOPOLAMINE  SLEEP,  and  also  actually 
can  with  it  induce  sleep  even  in  conditions  of  marked  mental  excite- 
ment, there  is  an  important  difference  between  the  hypnotic  action 
of  scopolamine  and  that  of  the  true  hypnotics.  The  primary  seat  of 
action  with  scopolamine  does  not  lie  in  the  centres  for  the  perception 
of  sensory  impressions,  by  an  action  on  which  the  true  hypnotics 
favor  the  process  of  falling  asleep,  for  scopolamine  primarily  depresses 
the  excitability  of  the  motor  centres.  When  the  scopolamine  action 
commences  to  develop,  the  patients  show  a  relaxation  of  their  muscles 
and  the  motor  unrest  ceases.  Only  after  this  do  the  patients  sink 
down  in  a  relaxed  position,  the  breathing  sometimes  becoming  slightly 
stertorous  on  account  of  the  relaxation  of  the  epiglottis  and  the  speech 
a  little  uncertain.  At  this  stage  the  patients  are  still  conscious  and 
are  sensible  of  visual  impressions,  etc.  After  this  sleep  ensues,  but 
is  often  preceded  by  delusions,  hallucinations,  and  delirium. 

The  characteristic  relaxation  of  the  muscles  observed  in  the  earliest  phases 
of  the  scopolamine  action  and  the  efficiency  of  the  drug  in  combating  motor 
excitement  are  in  agreement  with  Ramm's  statement  that  in  dogs  this  drug 
quickly  depresses  the  cerebral  motor  centres  so  that  they  no  longer  respond 
to  electric  stimulation. 

This  drug  is  also  used  with  benefit  in  nervous  diseases  with  symp- 
toms of  motor  irritation,  and  especially  in  paralysis  agitans.  Its  use 
as  a  substitute  for  atropine  in  ophthalmologic  practice  will  be  dis- 
cussed in  another  chapter.  A  better  acquaintance  with  the  action  of 
morphine  is  also  necessary  before  the  use  of  scopolamine  in  combina- 
tion with  morphine  as  a  narcotic  for  surgical  procedures  and  as  an 
adjuvant  for  the  general  anaesthetics  may  be  discussed. 

THE  DANGERS  ASSOCIATED  WITH  THE  USE  OF  SCOPOLAMINE  lie  in  an 

extension  of  its  depressing  action  on  the  respiratory  centre,  as  also 
in  the  possibility  of  cardiac  failure.  In  general,  the  margin  between 
hypnotic  and  toxic  or  lethal  doses  of  scopolamine  is  quite  large  in 
dogs  as  well  as  in  man.  Dogs,  in  whom  1  mg.  is  an  efficient  doser 
sometimes  may  support  1  gramme  without  fatal  effect.  However,  in 


MORPHINE  29 

man,  as  also  has  been  observed  in  a  few  cases  with  the  dog,  the  individ- 
ual susceptibility  appears  to  vary  greatly.  In  conditions  of  pro- 
nounced psychical  excitement,  not  only  are  larger  doses  required,  but 
also  larger  doses  may  be  borne  without  harmful  results. 

In  the  PRACTICAL  EMPLOYMENT  OF  SCOPOLAMINE,  THE  VARIABLE 
ACTIVITY  OF  DIFFERENT  PREPARATIONS  has  been  found  quite  disturbing. 
This  is  due  to  the  great  difficulty  of  obtaining  preparations  of  scopola- 
mine  entirely  free  from  contamination  by  the  other  related  alkaloids, 
some  of  which  have  quite  different  and  in  part  antagonistic  pharmaco- 
logical actions.  Thus,  Atropa  belladonna  contains,  besides  seopola- 
mine,  another  alkaloid,  apo-atropine  (apatropine) ,  which  is  much  less 
powerfully  mydriatic  but  very  poisonous,  causing  pronounced  central 
excitation.  This  alkaloid  appears  often  to  be  present  as  a  contamina- 
tion in  preparations  of  scopolamine  (Robert}.  According  to  Kessel, 
it  is  easy  to  detect  the  presence  of  this  contamination  by  adding 
a  few  drops  of  a  solution  of  potassium  permanganate  to  the  suspected 
solution,  reduction  indicating  the  presence  of  this  particular  con- 
tamination. 

BIBLIOGRAPHY 

Erb:  Therapeut.  Monatshefte,  1887,  p.  252. 

Gnauck:    Charite-Analen,  1882,  vol.  8. 

Kessel :   Arch,  internal,  de  Pharmacodynamie  et  de  Ther.,  1906,  vol.  16. 

Robert:   Zeitschrift   f.   Krankenpflege,    1905,   vol.   27,   No.   2. 

Robert  u.  Sohrt:    Arch.  f.  exp.  Path.  u.  Pharm.,  1886,  vol.  22. 

Rochmann:    Arch,  internat.  de  Pharmacodynamie  et  de  Ther.,  vol.  13,  1903,  p.  99; 

Therapie  der  Gegemvart,  Mai,  1903. 
Ramm:   Inaug.-Diss.,  Dorpat,  1893. 
Schmidt,  E.:   Arch,  der  Pharmacie,  1892  and  1894. 
Wood:  Therapeutic  Gazette,  1885. 

MORPHINE  GROUP 

Among  the  manifold  forms  of  cerebral  narcosis  produced  by 
various  agents,  that  produced  by  morphine  is  singular  in  that  this 
drug  so  markedly  lessens  the  sensibility  to  pain.  On  the  other  hand, 
morphine  does  not  depress  the  excitability  of  the  cerebral  cortex  in 
anything  like  the  same  degree  as  do  the  narcotics  of  the  alcohol- 
chloroform  group  (see  p.  43  ff.) ,  for,  long  before  it  completely  abolishes 
the  cerebral  functions,  it  produces  such  marked  depression  in  the 
medulla,  especially  of  the  respiratory  centre,  that  death  ensues  before 
reflex  excitability  of  the  cord  disappears.  The  effects  of  morphine 
thus  differ  from  those  of  alcohol  and  choloroform  in  that  the  different 
portions  of  the  central  nervous  system  are  affected  by  it  in  a  different 
sequence.  With  chloroform,  alcohol,  etc.,  first  the  cerebrum,  then 
the  cord,  and  last  of  all  the  respiratory  centres  are  depressed,  while 
with  morphine  the  depression  of  the  respiratory  centres  occurs  simul- 
taneously with  [or  previously  to — TR.]  the  depression  of  the  cere- 
brum, while  the  reflex  excitability  of  the  cord  is  depressed  in  a  far 
slighter  degree. 


30     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

This  great  sensitiveness  to  very  small  doses  manifested  by  certain 
of  the  functional  tracts  of  the  cerebral  cortex  is  of  fundamental  im- 
portance for  the  therapeutic  usefulness  of  morphine,  for  perception 
of  pain  is  diminished  by  doses  which  scarcely  affect  the  motor  centres 
and  which  have  no  appreciable  influence  on  the  perception  of  ordinary 
sensations.  Such  specificity  of  action  is  not  shown  by  the  substances 
of  the  alcohol-chloroform  group,  for  with  them  such  analgesic  effects 
are  obtained  only  by  doses  which  also  cause  sleep.  The  respiratory 
centre  and  those  closely  connected  sensory  centres  which  control  the 
cough  reflex  show  this  same  special  sensitiveness  to  morphine.  Conse- 
quently, morphine  is  primarily  a  pain  and  a  cough  reliever,  while  its 
hypnotic  effects  are  produced  only  by  larger  doses. 

Morphine  is  derived  from  opium,  the  inspissated  juice  of  the  unripe  fruit 
of  the  poppy,  Papaver  somniferum.  The  opium  used  medicinally  comes  chiefly 
from  Asia  Minor  and  the  Balkan  peninsula,  but  opium  is  also  produced  in 
India,  China,  Persia,  and  elsewhere.  Even  the  common  field  poppy  contains 
opium,  but  not  in  quantities  sufficient  to  justify  its  commercial  preparation 
(Thorns). 

Opium  contains  a  large  number  of  alkaloids,  of  which  about  twenty  have 
thus  far  been  isolated.  However,  the  main  bulk  of  these  alkaloids  is  made  up 
by  morphine,  and  the  other  alkaloids  are  either  physiologically  inert  or  else 
present  in  such  small  quantities  that  they  may  be  disregarded.  Consequently 
the  actions  of  opium  are  essentially  those  of  morphine  slightly  modified  by  the 
other  alkaloids  present.  The  usual  morphine  content  of  opium  is  about  10 
per  cent.,  but  occasionally  rises  to  as  high  as  20  per  cent. 

Of  the  other  alkaloids,  amounting  to  about  5  per  cent,  in  all,  the  greater 
portion,  about  4  per  cent.,  is  the  inert  narcotine.  Papaverine,  weakly  narcotic, 
codeine,  and  thebaine,  closely  resembling  strychnine,  are  present  in  only  minute 
amounts.  In  opium  these  alkaloids  are  combined  with  meconic  acid  and  are 
accompanied  by  resinous  substances. 

Morphine  is  present  in  all  portions  of  the  poppy  plant,  but  as  the  heads 
ripen  the  morphine  disappears  and  the  seeds  contain  no  morphine. 

Morphine,  with  the  empiric  formula  Ci7H10NO3,  is  the  first  alkaloid  which  was 
prepared  in  pure  form  (Sertiimer,  1804-16),  and  is  a  monovalent  tertiary  base. 
While  its  constitution  has  not  been  definitely  established,  the  last  few  years  have 
nearly  solved  this  problem,  and  the  morphine  alkaloids  are  assumed  to  be 
derivatives  of  a  hydrated  phenanthrene  nucleus  which  contains  one  alcohol  and 
one  phenol  hydroxyl  radical  with  the  third  oxygen  in  special  bridge-like 
combination. 


Phenanthrene. 


3,  6  Dioxy  5,  6,  7, 
8,  9,  10  Hexa- 

hydro- 
phenanthrene. 


CH3-N 


OH 


CH2 


Morphine  (?). 


MORPHINE  31 

In  codeine  the  alcoholic  hydroxyl  is  methylated,  and  in  thebaine 
both  hydroxyls  are  methylated. 

Free  morphine  is  but  slightly  soluble  in  water,  more  so  in  alcohol,  acetic 
ether,  chloroform,  and  amyl  alcohol.  Its  salts  are  readily  soluble  in  water 
and  readily  crystallizable,  the  hydrochlorate  and  sulphate  being  the  ones  most 
used.  The  addition  of  ammonia  or  of  the  caustic  alkalies  to  solutions  of  its 
salts  precipitates  the  free  base,  which  is  redissolved  by  an  excess  of  NaOH  or 
KOH.  It  is  readily  oxidized  by  oxidizing  agents. 

In  vertebrates  the  susceptibility  to  morphine  increases  with  the 
higher  development  of  the  central  nervous  system.  In  order  to 
produce  distinct  effects  in  a  frog  of  30  gm.  weight,  doses  must  be 
administered  which  would  seriously  poison  adult  human  beings.  Ob- 
servations on  the  frog  show  that  the  action  of  this  drug  is  most 
pronounced  in  those  functional  tracts  which  are  most  highly  developed 
and  which  ontogentically  are  last  to  develop. 

EFFECTS  ON  THE  FROG. — If  0.03-0.05  gm.  of  morphine  hydro- 
chlorate  be  injected  into  a  frog,  the  first  effect  noted  is  the  cessation 
of  spontaneous  movements.  The  frog  no  longer  seeks  to  escape, 
although  when  stimulated  he  can  carry  out  well-coordinated  and 
powerful  movements,  at  this  stage  behaving  as  if  decerebrated.  Next 
disturbances  in  the  coordination  of  complex  movements  develop.  The 
frog  no  longer  sits  in  the  normal  position,  and  jumps  clumsily,  be- 
having as  if  the  corpora  quadrigemina  had  been  removed.  As  the 
toxic  action  develops  still  further,  the  frog  is  no  longer  able  to  leap, 
although  still  able  to  turn  over  when  placed  on  its  back,  but  only 
slowly  and  helplessly,  as  after  removal  of  the  cerebellum.  Finally, 
when  laid  on  the  back,  it  can  no  longer  turn  over,  respiration  ceases,  and 
the  cranial  nerve  reflexes  (e.g.,  cornea!  reflex)  disappear,  although  the 
spinal  reflexes  persist.  At  this  stage  the  condition  is  similar  to  that 
of  a  frog  after  the  medulla  has  been  removed.  Finally,  the  spinal 
reflexes  also  disappear.  In  the  first  stage  of  the  action  of  morphine, 
the  depression  affects  different  parts  of  the  central  nervous  system 
successively,  commencing  with  the  cerebrum,  much  as  occurs  when 
different  portions  of  the  central  nervous  system  are  removed  in  regular 
order  (Witkowski).  Naturally,  the  elimination  of  the  different  func- 
tional tracts  does  not  take  place  so  precisely  under  the  influence  of 
the  drug  as  after  operative  removal,  for  the  narcotic  action  in  one 
part  of  the  brain  commences  before  it  has  been  completely  developed 
in  another  portion.  This  characteristic  starting  of  the  depressant 
action,  first  in  the  highest  centres  and  later  in  the  lower  ones,  occurs 
also  in  the  higher  animals. 

The  second  stage  of  morphine  action,  the  stage  of  tetanus,  on  the 
contrary,  can  be  observed  in  its  full  development  only  in  the  cold- 
blooded animals,  which,  on  account  of  their  slight  need  of  oxygen, 
can  survive  the  cessation  of  the  respiration.  The  increased  reflex 
excitability  first  manifests  itself  in  the  frog  by  so-called  spasmodic 


32     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

respiration,  groups  of  deep  and  rapid  respirations  being  separated 
by  long  pauses.  The  spinal  reflex  excitability,  which  in  the  narcotic 
stage  was  so  depressed  and  later  paralyzed,  returns  again  and  is 
increased  to  such  a  degree  that  tactile  stimuli  excite  tonic  convulsions, 
just  as  is  the  case  after  strychnine.  In  principle,  this  second  tetanic 
stage  is  indicated  to  some  extent  throughout  the  animal  kingdom, 
but  the  higher  the  development  of  the  central  nervous  system  the 
more  does  this  tetanic  action  fall  in  the  background.  If,  however, 
dogs  which  have  received  large  doses  of  morphine  are  kept  alive  by 
artificial  respiration,  a  markedly  increased  reflex  excitability  of  the 
cord  can  develop  (Lenhartz) .  In  man,  too,  abnormal  reflex  excitability 
may  be  observed  after  small  doses,  and  in  poisoning,  especially  in 
children,  convulsions  may  occur.  On  the  other  hand,  in  the  lower 
vertebrates  the  narcotic  action  is  far  less  evident,  morphine  acting  in 
fishes  purely  as  an  excitant  like  strychnine,  without  producing  any 
preliminary  depressing  action. 

IN  THE  MORE  HIGHLY  DEVELOPED  ANIMALS,  the  development  of  the 
morphine  action  does  not  take  place  so  diagrammatically  as  in  the 
frog.  Above  all,  among  the  different  species,  there  are  not  only  dif- 
ferences in  susceptibility  to  the  drug,  but  also  qualitative  differences 
in  the  reaction  of  the  nervous  system  to  morphine.  After  adminis- 
tration of  this  drug  to  dogs,  almost  always  salivation,  retching,  vomit- 
ing, and  defecation  occur.  After  some  restlessness  at  the  start,  a 
quieting  effect  is  noted,  and  then  the  animals  sleep  for  hours.  When 
large  doses  have  been  administered,  increased  reflexes  and  twitching 
of  the  muscles  may  be  noted.  With  rabbits,  rats,  mice,  and  birds, 
narcosis  is  induced,  but  with  cats,  horses,  and  cattle,  the  drug  causes 
great  restlessness  and  a  tendency  to  motor  activity,  with  staggering 
and  convulsions,  but  never  a  true  narcosis  (Frohner,  Hess}.  Con- 
traction of  the  pupils  occurs,  as  a  rule,  in  those  species  which  are 
narcotized  by  the  drug,  and  dilatation  in  those  which  are  excited. 

This  difference  in  the  reaction  to  morphine,  observed  in  different 
animal  species,  is  of  interest  because  in  certain  especially  predisposed 
human  beings  morphine  may  excite  instead  of  quieting  the  cerebral 
functions.  In  most  human  beings,  however,  a  general  sedative  effect 
and  desire  for  sleep  result  from  doses  of  from  0.01  to  0.02  gm.,  while, 
after  toxic  doses,  drowsiness  and  sleep  are  gradually  succeeded  by  a 
state  of  profound  unconsciousness. 

The  most  important  action  of  small  doses  of  morphine  is  the  DE- 
PRESSION OF  THE  ABILITY  TO  PERCEIVE  PAIN.  In  the  dog  there  results 
a  stage  of  stupor  and  unwillingness  to  move,  and  the  power  of  pain 
perception  is  almost  entirely  lost,  although  the  ordinary  sensory  per- 
ception is  hardly  affected,  nor  is  there  any  tendency  to  fall  asleep. 
The  motor  regions  of  the  cortex  remain  excitable  even  in  deep  narcosis. 
Hitzig  observed  no  diminution  of  their  susceptibility  to  electric  stimu- 
lation, even  after  large  doses.  In  fact,  with  moderate  doses  such 


MORPHINE  33 

stimulation  was  more  regularly  followed  by  a  motor  effect  than  under 
normal  conditions,  although  painful  procedures  (e.g.,  twisting  the 
dura)  no  longer  caused  whining  or  struggling,  although  the  corneal 
and  other  reflexes  were  still  present. 

In  man  also  the  perception  of  pain  is  depressed  long  before  the 
sensorium  is  affected.  Formerly  it  was  believed  that  this  was  due 
to  a  peripheral  action  of  morphine  on  the  peripheral  sensory  organs, 
but  careful  investigation  of  the  condition  of  the  algesic  and  the  tactile 
senses  has  shown  that  morphine  causes  no  diminution  of  the  sensibility 
of  the  peripheral  sensory  organs,  for  the  site  of  injection  is  no  less 
sensitive  than  the  corresponding  part  on  the  other  side  of  the  body 
(Jolly  u.  Hilsmann).  We  are  dealing,  therefore,  with  a  central 
hypalgesia. 

WITH  NO  OTHER  DRUG  CAN  SUCH  AN  ISOLATED  ACTION  ON  THE  PAIN- 
PERCEIVING  CENTRES  BE  SECURED,  ALTHOUGH  A  SOMEWHAT  SIMILAR 
EFFECT,  BUT  A  SLIGHTER  ONE,  IS  PRODUCED  BY  DRUGS  OP  THE  ANTIPYRINE 
GROUP. 

Doses  as  small  as  5  mg.  of  morphine  hydrochloride  are  sufficient 
to  lessen  perception  of  pain  in  adult  patients  who  have  not  become 
accustomed  to  the  drug.  On  the  other  hand,  0.01  gm.  is  not  enough 
to  produce  an  hypnotic  effect  in  all  individuals.  Ordinary  disagree- 
able sensations,  as  those  of  fatigue,  hunger,  or  discomfort,  as  well 
as  pain,  are  relieved  by  morphine,  euphoria  resulting,  and  herein  lies 
the  great  danger  of  habituation  to  its  use.  A  closer  psychophysical 
analysis  of  these  phenomena  has  demonstrated  that  the  perception  of 
stimuli  from  without  is  not  at  all  depressed  by  small  doses  of  morphine, 
but  is,  on  the  contrary,  distinctly  favored  (Krdpelin).  This  stimu- 
lation of  certain  mental  processes,  which  in  normal  individuals  reaches 
its  full  development  about  half  an  hour  after  administration  of 
0.01  gm.  of  morphine,  explains  the  ability  of  morphine  habitues  to  do 
hard  mental  work  so  long  as  the  morphine  is  acting.  Other  psychical 
processes,  in  which  the  accomplishment  of  a  motor  reaction  plays  a 
prominent  part,  as,  for  example,  the  performance  of  a  muscular 
reaction  after  a  given  stimulation,  are  from  the  start  retarded  by 
morphine.  This  interference  with  motor  processes  is  responsible  for 
the  quietness  which  develops  after  morphine  long  before  somnolence 
does,  and  also  for  the  tendency  to  dream  peacefully  and  quietly,  which 
is  so  characteristic  of  opium  intoxication  and  which  contrasts  so 
strongly  with  the  condition  produced  by  alcohol. 

Besides  the  above-mentioned  depression  of  the  central  perception 
of  pain  which  is  the  chief  indication  for  the  use  of  morphine,  this 
drug  exerts  a  similar  ELECTIVE  ACTION  ON  THE  RESPIRATORY  CENTRE, 
the  respirations  being  rendered  quieter,  deeper,  and  slower  by  small 
doses.  This  will  be  more  fully  discussed  later  (p.  337  ff.). 

The  quieting  effect  exerted  by  morphine  on  intestinal  peristalsis, 
which  occurs  when  the  drug  is  used  for  relief  of  pain  or  cough,  may 
3 


34     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

be  considered  as  a  side  action  in  so  far  as  it  is  an  undesired  one, 
leading  to  constipation. 

A  number  of  other  side  actions  may  be  considered  from  a  common 
point  of  view,  as  they  depend  on  the  depression  of  certain  central 
inhibitions  which  lessen  the  tone  of  the  oculomotorius  and  the  vagus 
centres,  which  inhibitions  are  in  part  removed  by  the  action  of  mor- 
phine just  as  is  the  case  during  normal  sleep. 

Among  these  are  the  contraction  of  the  pupil  and  the  narrowing 
of  the  cleft  between  the  lids  (compare  section  on  pharmacology  of 
the  eyes)  and  the  increased  tone  of  the  vagus  centre  which  causes  slow- 
ing of  the  heart,  which,  however,  occurs  only  after  unusually  large 
doses.  Of  similar  origin  is  the  spasmodic  contraction  of  the  bladder 
sphincter,  which  is  in  part  the  result  of  a  central  interference  with  its 
sympathetic  nervous  inhibition  and  which  in  human  beings  may 
prevent  micturition  in  spite  of  a  strong  desire.  In  guinea-pigs  this 
particular  effect  may  be  so  pronounced  that  at  times  rupture  of  the 
bladder  and  death  ensue  (Tappeiner). 

The  NARROWING  OF  THE  PUPIL  is  of  diagnostic  importance.  It  is 
certainly  not  the  result  of  a  local  action,  for  it  does  not  result  when  a 
morphine  solution  is  dropped  into  the  eye.  This  myosis  is,  however, 
characteristic  only  of  the  narcotic  stage,  and  is  succeeded  by  dilatation 
when  the  tetanic  stage  develops.  As  above  mentioned,  it  does  not 
occur  in  those  animals  whose  higher  centres  are  excited  by  morphine, 
for  in  them  the  pupils  are  dilated.  Finally,  in  the  last  stages  of 
morphine  poisoning,  the  asphyxia  causes  mydriasis.  It  follows,  there- 
fore, that,  although  the  pupils  are  usually  contracted  when  morphine 
has  been  taken,  the  absence  of  this  symptom  in  no  way  excludes 
morphine  poisoning. 

After  small  doses  VOMITING  seldom  occurs,  and  then  only  in  espe- 
cially susceptible  individuals,  and  small  doses  of  atropine  ((T.2  mg.), 
as  a  rule,  will  prevent  it  entirely.  After  large  doses  nausea  and  vomit- 
ing are  very  commonly  the  initial  symptoms  of  the  poisoning. 

The  CIRCULATION  is,  generally  speaking,  but  slightly  affected  by 
morphine.  In  man  a  passing  acceleration  of  the  pulse  is  followed  by 
moderate  retardation.  In  the  dog,  on  the  other  hand,  the  slowing 
of  the  pulse  is  very  pronounced  and  is  due  to  augmentation  of  the 
central  vagus  tone.  In  other  particulars  in  morphine  poisoning  the 
circulation  suffers  only  secondarily  as  a  result  of  a  depression  of  the 
heart  from  the  asphyxia  and  of  a  paralysis  of  the  vasomotor  centres. 
On  the  other  hand,  the  depression  of  the  respiration  is  very  pronounced 
from  the  start  and  colors  the  whole  picture. 

ACUTE  MORPHINE  POISONING. — Toxic  doses  range  from  0.03-0.05 
gm.  of  morphine  hydrochlorate,  0.2  gm.  being  the  minimum  lethal 
dose  for  adults,  while  0.3-0.4  gm.  may  be  considered  as  the  average 
lethal  dose  for  individuals  unaccustomed  to  its  use.  Poisoning  is 
usually  the  result  of  taking  the  drug  by  mistake  or  of  errors  in  pre- 


MORPHINE  35 

scribing  or  compounding  or  when  the  drug  is  taken  with  suicidal 
intent.  Three-quarters  of  all  the  cases  of  morphine  or  opium  poison- 
ing occur  in  children  under  five  years  of  age,  which  fact  is  explained 
by  the  great  susceptibility  of  children  to  this  drug.  In  small  children 
even  the  administration  of  decoctions  of  dried  unripe  poppy  heads  as 
soothing  potions  may  cause  poisoning.  Furthermore,  inasmuch  as 
morphine  is  excreted  in  the  milk,  poisoning  of  nursing  infants  may 
result  from  the  consumption  of  morphine  by  the  wet-nurse.  On  the 
other  hand,  the  foetus  in  utero  is  very  resistant  to  morphine,  as  it 
does  not  breathe  on  its  own  account,  and  consequently  the  administra- 
tion of  this  drug  during  pregnancy  carries  little  risk,  except  that, 
when  administered  shortly  before  delivery,  it  may  jeopardize  respira- 
tion of  the  child  after  birth. 

In  morphine  poisoning  a  condition  of  deep  coma  developing  in  the 
course  of  15-30  minutes  is  characteristic.  Large  doses  cause  a  deep 
sleep  which  at  the  start  may  be  effectively  combated  by  the  application 
of  external  stimuli,  but  gradually  the  tendency  to  sleep  is  irresistible, 
and  the  patient  passes  into  a  condition  of  coma  in  which  his  response 
to  sensory  stimulation  progressively  becomes  more  faulty  and  finally 
complete  unconsciousness  and  deep  coma  develop.  The  respiration 
gradually  becomes  more  and  more  infrequent,  irregular,  interrupted, 
and  rattling,  and  the  skin  becomes  pale  and  cold,  and  the  face  cya- 
notic,  but  the  pulse  continues  of  good  force  for  a  long  time.  Finally 
all  reflexes  disappear,  the  infrequent  respirations  grow  progressively 
more  shallow,  outspoken  Cheyne-Stokes  respiration  often  occurring, 
and  death  occurs  as  a  result  of  the  cessation  of  breathing,  and,  as 
the  vasomotor  centres  also  are  paralyzed,  the  blood-pressure  and  the 
temperature  of  the  body  fall  markedly.  As  a  rule,  the  pupils  remain 
contracted  to  the  end,  while  sometimes  death  is  preceded  by  convul- 
sions. In  less  severe  cases  the  coma  may  pass  off,  but  often  the 
patients,  after  a  temporary  improvement,  sink  back  again  into  a 
comatose  condition.  When  recovery  occurs,  constipation  and  diffi- 
culty in  urination  persist  for  some  time  after  the  patient  has  recov- 
ered from  the  deep  sleep,  which  may  last  for  a  day  or  longer. 

TREATMENT. — In  connection  with  the  treatment  of  acute  morphine 
poisoning  it  is  especially  important  to  remember  that,  although  vomit- 
ing almost  always  occurs  spontaneously  before  the  coma  develops,  the 
excitability  of  the  vomiting  centre  is  so  rapidly  depressed  as  the 
narcosis  develops  that  emetics  cannot  cause  vomiting.  Consequently, 
in  cases  of  poisoning  by  morphine  or  opium,  it  is  essential  that  stom- 
ach lavage  be  practised  for  the  purpose  of  removing  any  of  the  poison 
not  yet  absorbed.  Inasmuch  as  morphine  after  absorption  from  the 
stomach,  or  when  administered  subcutaneously,  is  excreted  again  into 
the  stomach,  morphine  may  be  found  there  even  15  or  18  hours  after 
its  administration,  and  therefore  lavage  should  be  practised  even 
many  hours  after  the  administration  of  the  drug.  This  holds  good 


36      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

also  for  cases  in  which  the  drug  has  been  administered  subcutaneously. 
As  the  drug  is  also  excreted  into  the  intestine,  the  attempt  should  be 
made  to  empty  the  bowels  by  cathartics  and  enemata.  Attempts  to 
render  unabsorbed  portions  of  the  morphine  insoluble  by  administer- 
ing tannic  acid  produce  but  slight  effects.  On  the  other  hand,  it  is 
possible  to  destroy  morphine  in  the  stomach  by  lavage  with  0.4  per 
mille  solution  of  potassium  permanganate  or  by  the  administration  of 
about  0.1  gm.  of  this  salt. 

In  addition  to  these  measures,  the  treatment  is  symptomatic,  hav- 
ing as  its  objects  the  prevention  of  the  deepening  of  the  comatose 
condition  and  above  all  the  prevention  of  the  threatening  cessation  of 
respiration.  For  this  reason  the  attempt  is  made  to  keep  the  patient 
awake  until  the  sleep  becomes  so  deep  as  to  render  this  impossible. 
For  this  purpose  one  leads  him  about,  applies  various  stimuli  to  the 
skin,  and  administers  drugs  which  stimulate  the  central  nervous  sys- 
tem, such  as  camphor,  black  coffee,  etc.  If,  in  spite  of  such  effects, 
the  coma  deepens,  subcutaneous  injections  are  made  of  atropine,  our 
most  powerful  chemical  stimulant  for  the  respiratory  centre.  This 
antidotal  treatment  has  proved  itself  to  be  life  saving  in  many 
cases  of  poisoning  in  human  beings,  if  the  dosage  of  atropine  is  cor- 
rectly determined,  and  similar  results  have  been  obtained  in  experi- 
ments on  animals.  The  maximum  dose  should  be  injected  and 
frequently  repeated,  the  behavior  of  the  respiration  serving  as  a  guide. 

THERAPEUTIC  USES. — As  a  means  of  relieving  pain  morphine  can 
be  replaced  by  no  other  drug.  The  ordinary  dosage  ranges  from 
0.003-0.03  gm.  per  dose,  0.1  gm.  per  day  being  the  maximal  dose 
under  ordinary  conditions.  The  detailed  discussion  of  its  field  of 
usefulness  in  various  internal  and  surgical  diseases,  especially  in  the 
treatment  of  different  types  of  colic,  neuralgias,  etc.,  belongs  to  the 
clinician.  No  physician  would  be  willing  to  do  without  this  most 
valuable  of  all  means  of  giving  relief  IN  PAINFUL  CONDITIONS  of  an 
acute  nature,  or  in  those  hopeless  chronic  cases  in  whom  even  the 
danger  of  acquiring  the  morphine  habit  must  be  looked  upon  as  the 
lesser  evil.  As  is  well  known,  however,  this  danger  must  never  be 
forgotten,  for,  in  addition  to  blunting  the  perception  of  pain,  mor- 
phine produces  a  condition  of  euphoria  which  carries  with  it  the 
temptation  to  a  chronic  abuse  of  the  drug  even  after  the  original 
occasion  for  its  use  has  disappeared.  The  subcutaneous  injection 
(introduced  in  1855  by  the  American,  Wood)  of  from  Va  to  1  c.c. 
of  a  1  to  2  per  cent,  solution  is  the  best  means  of  securing  rapid 
relief  of  pain.  Frequently  about  0.2  mg.  of  atropine  sulphate  is 
added  to  such  injections.  It  should  be  remembered,  however,  that  it 
is  particularly  this  form  of  administering  morphine  which  opens  the 
path,  to  the  development  of  morphine  habituation,  and  consequently 
it  is  most  necessary  that  the  physician  should  exercise  caution  in  thus 
administering  the  drug. 


MORPHINE  37 

Another  indication  for  the  use  of  morphine  is  for  the  relief  of  a 
COUGH  or  of  CARDIAC  DYSPNCEA.  The  significance  and  importance  of 
this  sedative  action  on  the  respiratory  centre  will  be  further  discussed 
in  another  connection  (see  p.  337). 

In  the  treatment  of  SLEEPLESSNESS  morphine  is  not  so  valuable  as 
the  hypnotics  of  the  alcohol  group  in  all  those  cases  in  which  sleep  is 
prevented  by  psychic  excitement  or  nervous  restlessness.  Morphine 
should  be  used  as  an  hypnotic  only  when  pain,  coughing,  or  dyspnoea 
prevents  the  falling  asleep.  Somewhat  larger  doses  of  morphine  may 
be  used,  however,  for  the  relief  of  conditions  of  motor  excitement  in 
the  insane  and  in  cases  of  poisoning  by  substances  which  cause  cerebral 
excitement.  Among  such  delirium  tremens  and  poisoning  by  atropine 
are  especially  to  be  mentioned. 

OPIUM. — Where  it  is  desirable  to  have  the  effects  of  morphine 
develop  somewhat  more  slowly  or  where  the  local  effect  on  the  alimen- 
tary canal  is  the  desideratum,  it  is  the  general  rule  to  make  use  of  the 
galenic  preparations.  Opium  itself,  containing  from  12  to  12!/£  per 
cent,  of  morphine,  is  used  in  dosage  of  from  0.02  to  0.1  gm.,  0.15  and 
0.5  gm.  being  the  maximal  single  and  24-hour  doses.  The  extracts 
containing  20  per  cent,  of  morphine  are  to  be  used  in  somewhat  smaller 
doses.  Dover's  powder  (opium  1,  ipecac  1,  sugar  of  milk  8),  the  tinc- 
ture, and  the  deodorized  tincture,  each  containing  10  per  cent,  of 
opium,  and  the  camphorated  tincture,  containing  .4  per  cent,  of  opium, 
are  the  more  commonly  used  preparations. 

The  OTHER  ALKALOIDS  present  in  opium  (see  p.  30)  have  been 
but  little  investigated,  particularly  in  respect  to  their  actions  in 
man.  Narcotine,  which  after  morphine  is  the  one  present  in  largest 
quantities,  certainly  has  little  pharmacological  action,  while  the  others, 
which  are  present  in  smaller  quantities,  all  show  a  far  weaker  narcotic 
action  than  morphine.  On  the  other  hand,  they  all  exert  a  much  more 
pronounced  stimulating  action  on  the  spinal  cord,  so  that  many  of 
them,  when  given  in  toxic  doses,  produce  convulsions  of  spinal  origin 
which  are  not  preceded  by  any  narcotic  action  on  the  cerebrum  similar 
to  that  produced  by  morphine  (v.  Schroder) .  The  respiratory  centre 
is  also  stimulated  by  some  of  these  alkaloids.  Consequently  the  mix- 
ture of  all  of  the  opium  alkaloids  produces  a  weaker  narcotic  action 
and  less  sedative  effects  on  the  respiratory  centre  than  the  morphine 
contained  in  it  when  given  by  itself  (Wertheimer-Raffalowich,  Lowi, 
Bergien).  Clinical  experience  on  human  beings  appears,  however,  to 
indicate  that  the  mixture  of  all  the  opium  alkaloids  is  as  efficient  for 
the  relief  of  pain  as  is  pure  morphine  in  corresponding  amounts. 

Sahli  has  recently  recommended,  under  the  name  of  PANTOPON,  a 
mixture  of  the  hydrochlorates  of  all  the  opium  alkaloids,  which  is 
soluble  in  water,  claiming  that  with  it  one  can  obtain  the  effects  of 
morphine  modified  by  the  actions  of  these  other  alkaloids.  It  is 
essentially  a  preparation  of  opium  from  which  the  useless  constituents 


38     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

have  been  removed  and  which  may  be  injected  subcutaneously.  It 
contains  the  same  alkaloids  in  the  same  relative  proportions  as  does 
opium,  but  in  about  fivefold  concentration,  so  that  0.02  gm.  of  pan- 
topon  corresponds  to  about  0.01  gm.  morphine  hydrochlorate. 

CODEINE. — If  in  morphine  the  hydrogen  of  the  alcohol  hydroxyl 
group  is  replaced  by  alkyl  radicals,  the  so-called  codeines  are  obtained. 
The  most  important  of  these,  the  methyl  ester  of  morphine,  codeine 
itself,  is  present  in  opium  in  the  small  proportion  of  about  0.1  per 
cent.  Under  the  trade  names  of  dionin  and  peronin,  the  methyl  ester 
and  benzoyl  ester  have  been  introduced  into  use.  The  codeines  differ 
from  morphine  principally  in  the  fact  that  the  action  on  the  respira- 
tory centre  persists  while  the  narcotic  action  on  the  higher  cerebral 
centres  is  markedly  diminished.  According  to  v.  Schroder,  the 
power  of  increasing  the  reflex  excitability  of  the  cord  is  increased. 
These  drugs  are  valuable  substitutes  for  morphine  in  the  treatment 
of  coughs. 

In  the  last  few  decades  codeine  has  acquired1  a  constantly  increas- 
ing importance  in  the  treatment  of  coughs.  It  is  now  manufactured 
synthetically  from  morphine,  and  is  consequently  much  cheaper  than 
when  it  had  to  be  prepared  from  opium.  It  occurs  in  the  form  of 
colorless  crystals,  soluble  with  difficulty  in  water,  and  forming  readily 
crystallizable  salts,  of  which  the  readily  soluble  phosphate  is  the  best 
for  therapeutical  use. 

In  man,  0.03-0.06  gm.  of  codeine  produces  about  the  same  effects 
in  relieving  cough  as  0.005-0.01  gm.  of  morphine,  while  it  is  about 
20  times  less  poisonous.  Therapeutic  doses  also  produce  some  quieting 
effect,  but  even  large  doses  do  not  cause  actual  narcosis.  On  the 
contrary,  in  the  relatively  rare  cases  of  idiosyncrasy  only  restlessness 
and  slight  muscle  twitchings  and  mydriasis  have  been  observed.  In 
animal  experiments  the  narcotic  actions  on  the  cerebrum  are  so  slightly 
expressed  that  the  older  investigators  overlooked  them  when  moderate 
doses  were  administered,  while  after  larger  doses  its  property  of  caus- 
ing tetanus  is  alone  evident. 

Codeine,  therefore,  may  be  looked  upon  as  a  very  mildly  acting 
morphine.  By  its  use  in  place  of  morphine  the  danger  of  the  develop- 
ment of  the  habit  may  be  avoided  in  cases  of  chronic  coughs.  It 
appears  to  be  less  suitable  as  a  means  of  relieving  pain  or  as  a 
general  sedative,  and  should  be  used  for  such  purposes  as  a  substitute 
for  morphine  only  in  children. 

The  ethyl  ester  of  morphine,  DIONIN,  closely  resembles  codeine. 
On  the  other  hand,  diacetyl  morphine,  obtained  by  the  substitution 
of  acetic  acid  radicals  for  the  hydrogen  of  both  of  the  hydroxyl  groups 
of  morphine,  and  known  as  HEROIN,  possesses  a  far  more  powerful 
pharmacological  action.  Even  in  doses  of  a  few  milligrammes  it  exerts 
a  sedative  action  on  the  respiratory  centre,  but  in  laboratory  experi- 
ments even  comparatively  small  doses  produce  dangerous  toxic  effects 


MORPHINISM  89 

on  the  medullary  centres.  The  dose  of  dionin  ranges  from  0.03-0.05 
gin.  per  dose  and  that  of  heroin  from  0.003-0.005  gm.  ( !)  per  dose. 
In  judging  of  the  value  of  these  substitutes  for  morphine,  the  most 
important  point  to  determine  is  the  degree  in  which  they  may  cause 
habituation  similar  to  that  caused  by  morphine. 

MORPHINISM. — This  brings  us  to  a  discussion  of  the  most  serious 
harmful  effect  of  morphine  and  opium,  the  development  of  chronic 
morphinismus  when  the  drug  is  continually  administered.  When 
morphine  is  chronically  misused,  it  is  taken  not  only  for  the  purpose 
of  relieving  pain  or  coughs,  but  the  patient  takes  it  just  as  soon  as 
lie  feels  tired  or  uncomfortable,  and,  when  it  is  thus  repeatedly  taken, 
habituation  gradually  develops  so  that  the  dose  must  be  increased 
in  order  to  obtain  the  same  effects.  If  the  habit  has  thus  been  acquired, 
as  soon  as  there  is  an  interruption  of  its  regular  administration 
"abstinence"  symptoms  develop,  and  the  patient  suffers  from  a 
general  feeling  of  distress  and  becomes  restless  and  consequently  has 
recourse  all  the  oftener  to  the  drug  in  order  that  he  may  again  be 
quieted  and  able  to  perform  mental  tasks.  The  rapidity  with  which 
the  dose  must  be  increased  varies  in  different  individuals,  and  the 
daily  consumption  of  one  or  two  grammes  of  morphine  by  a  morphin- 
ist  or  even  as  much  as  four  grammes  is  no  great  rarity.  Sooner  or 
later,  depending  on  the  individual  resistance,  the  consumption  of  such 
amounts  leads  to-  serious  psychical  disorders  and  to  disturbances 
in  the  functions  of  all  the  organs.  The  skin  becomes  dry  and  rough, 
but  at  times  there  is  a  tendency  to  profuse  sweating.  The  digestive 
apparatus  in  particular  suffers  seriously,  catarrh  of  the  stomach  and 
intestines,  constipation,  diarrhoea,  etc.,  developing.  Emaciation  and 
anaemia,  often  accompanied  by  albuminuria  and  glycosuria,  are  among 
the  other  harmful  effects-  of  this  habit.  When  the  attempt  is  made  to 
withdraw  the  drug,  severe  "abstinence  "  symptoms  appear,  and  the 
patient  suffers  from  restlessness  and  sleeplessness,  from  depression 
accompanied  by  a  feeling  of  anxiety,  or  he  may  become  extremely 
excited,  or  nausea  and  diarrhoea  or  even  collapse  may  complicate  the 
picture. 

It  is  the  euphoria  which  accompanies  the  therapeutic  effects  of 
morphine  which  makes  it  so  easy  to  acquire  the  habit.  Consequently 
the  danger  is  not  so  great  when  those  substitutes  for  morphine  are 
used  in  which  the  specific  effect  on  the  cerebrum  is  less  well  developed, 
for  then  there  is  no  such  temptation  to  increase  the  dose  over  that 
which  produces  the  desired  therapeutic  effects.  As  codeine  and  dionin 
do  not  produce  any  euphoria,  their  use  is  not  followed  by  their  abuse, 
but,  when  heroin  has  been  used  repeatedly,  serious  habituation  has 
been  observed  to  result. 

CAUSES  OF  TOLERANCE  TO  MORPHINE. — The  partial  explanation  of 
the  true  cause  of  habituation — i.e.,  an  explanation  of  the  reason  why 
it  is  necessary  constantly  to  increase  the  dose  in  order  to  obtain  the 


40     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

usual  effects — has  been  furnished  by  the  investigations  of  Faust, 
who  found  that  this  is  closely  related  with  the  fate  in  the  body  of 
morphine  and  its  congeners. 

Formerly  much  care  was  taken  to  isolate  morphine  in  unchanged, 
or  more  or  less  altered,  form  from  the  urine,  but  small  amounts  of 
the  unchanged  alkaloid  may  be  found  in  the  urine  only  when  very 
large  doses  have  been  taken,  and  even  altered  morphine  cannot  be 
detected  after  any  usual  doses.  On  the  other  hand,  Marme  found  in 
dogs,  and  later  Alt  found  in  human  beings,  that  morphine  injected 
subcutaneously  was  excreted  unchanged  into  the  stomach.  This  ex- 
cretion begins  a  few  minutes  after  the  injection  and  persists  as  long 
as  do  the  effects  of  the  morphine.  Using  more  exact  quantitative 
methods,  Tauber  found  in  the  faBces  about  41  per  cent,  of  the  mor- 
phine which  had  been  injected  in  the  course  of  10  days. 

The  condition  of  the  mucous  membranes  of  the  alimentary  canal  exerts 
considerable  influence  on  the  excretion  of  morphine,  hypersemia  and  increased 
secretion  of  the  epithelium  favoring  it.  By  the  local  action  of  alcohol  or  of 
the  irritating  decoctions  of  soap  bark  or  of  senega  root  on  the  alimentary 
canal,  McCrudden  was  able  to  increase  the  amount  of  morphine  excreted  in  the 
faeces  from  44-47  per  cent,  to  58-64  per  cent,  of  the  amount  which  had  been 
subcutaneously  injected  each  day.  His  results  suggest  that  in  morphine  poison- 
ing the  elimination  of  the  drug  could  be  favored  by  the  administration  of  such 
drugs,  just  as  the  attempt  is  made,  by  increasing  the  diuresis,  to  influence 
the  elimination  of  those  poisons  which  are  excreted  in  the  urine. 

In  Faust's  investigation  of  the  causes  of  habituation,  he  was  able  to 
demonstrate  that,  when  a  single  injection  of  morphine  is  given,  dogs  excrete, 
through  the  stomach  and  intestines,  about  70  per  cent,  of  the  amount  adminis- 
tered; he  also  found  that,  when  each  day  progressively  larger  doses  are  injected, 
the  amount  of  morphine  excreted  in  the  faeces  decreases,  so  that  finally,  in  spite 
of  the  daily  injection  of  ordinarily  lethal  doses,  no  morphine  appears  in  the 
excretions.  Inasmuch  as  after  death  the  organs  of  these  animals  contain 
only  very  small  quantities  of  the  poison,  Faust  was  justified  in  concluding  that, 
when  habituated  to  morphine,  the  organism  acquires  the  power  of  destroying 
much  larger  amounts  of  this  drug  than  an  individual  not  accustomed  to  its  use. 
On  the  other  hand,  according  to  Bouma,  when  codeine  is  repeatedly  administered, 
there  develops  neither  any  pronounced  insusceptibility  to  increasing  doses  nor 
any  increased  power  of  destroying  the  drug. 

The  results  of  these  investigations  have  thus  made  clear  one  of 
the  causes  of  tolerance,  but  it  is  not  probable  that  this  is  the  essential 
and  most  important  cause  for  the  insusceptibility  of  the  morphinist. 
Such  individuals  exhibit  their  insusceptibility  to  large  doses  of  mor- 
phine especially  when  these  are  administered  subcutaneously, — that 
is,  in  a  manner  which  favors  the  very  rapid  absorption  and  the  rapid 
arrival  of  the  morphine  in  the  central  nervous  system.  In  order  to 
explain,  by  an  exaggerated  or  increased  power  of  destruction,  the 
tolerance  to  such  amounts  of  poison  as  circulate  around  in  the  body 
in  the  first  short  period  following  its  injection,  it  would  be  necessary 
to  assume  that  the  poison  is  very  rapidly  destroyed.  The  experiments 
of  Rubsamen  with  rats  habituated  to  morphine  have  furnished  the 
necessary  data  to  determine  this  point.  He  was  able  to  render  -these 


MORPHINISM  41 

animals  tolerant  to  doses  twice  as  large  as  the  usual  lethal  dose. 
When  he  determined  how  much  morphine  was  still  present  in  the 
body  of  such  immunized  animals  at  a  time  when  symptoms  of  the 
poisoning  would  be  at  their  height  in  unhabituated  rats,  he  found 
that  it  was  still  possible  to  isolate  from  the  body  an  amount  of  the 
unchanged  poison  which  would  have  produced  severe  symptoms  of 
poisoning  in  animals  which  had  not  been  habituated  to  this  drug. 
The  animals  which  had  previously  received  numerous  injections  of 
morphine,  however,  showed  hardly  any  symptoms  worth  mentioning. 

From  these  findings  the  conclusion  must  be  drawn  that  the  repeated 
administration  of  morphine  results  in  the  development  of  a  lessened 
susceptibility  on  the  part  of  the  cells.  Against  this  conclusion  only 
one  criticism  may  be  urged, — namely,  that  it  is  possible  that  the  cen- 
tral nervous  system  acquires  in  a  particularly  high  degree  an  in- 
creased power  of  destroying  morphine  so  that  it  is  not  possible  for  the 
poison  to  reach  the  particularly  susceptible  nervous  elements  in  a 
sufficiently  high  concentration.  Special  experiments,  not  yet  pub- 
lished, which  were  undertaken  to  investigate  this  point  have  failed 
to  give  any  evidence  that  the  brains  of  immunized  animals  exhibit 
any  such  increased  power  of  destroying  morphine. 

However,  there  is  an  undeniable  connection  between  habituation 
to  and  the  more  rapid  destruction  of  certain  poisons  in  the  organism 
which  has  become  insusceptible  to  their  toxic  actions.  In  the  case 
of  certain  other  drugs  such  a  connection  can  be  demonstrated  (Flury). 
Thus,  Pringsheim  has  shown  that  alcohol  when  administered  daily  is 
combusted  more  rapidly  than  when  given  but  once.  However,  in  the 
case  of  alcohol  there  is  no  doubt  that  a  diminished  cellular  suscepti- 
bility develops,  for,  as  is  well  known,  the  alcoholic  exhibits  an  in- 
creased resistance  to  the  action  of  ether,  which  in  its  pharmacological 
actions  closely  resembles  alcohol,  in  spite  of  the  fact  that  ether  is  not 
at  all  combusted  in  the  organism  but  is  excreted  unchanged. 

Opiophagia,  or  opium  eating,  is  quite  analogous  to  morphinism.  The  abuse 
of  this  drug  has  spread  from  India  over  the  whole  of  Asia  and  Turkey, — in 
Persia  and  in  Turkey,  in  the  form  of  opium  eating,  in  China  and  in  all  lands 
whither  the  Chinese  have  immigrated,  in  the  form  of  opium  smoking.  In  this 
latter  form  of  indulgence,  for  which  in  China  opium  extracts  prepared  in  a 
special  manner  are  used,  undoubtedly  a  portion  of  the  morphine  passes  over  into 
smoke,  but  a  large  portion  is  destroyed,  and  consequently  the  harmful  effects 
of  opium  smoking  do  not  develop  so  rapidly  as  in  opium  eating.  In  both  cases, 
however,  in  the  course  of  time  the  symptoms  of  a  chronic  intoxication  develop 
which  closely  resemble  those  of  morphine  (v.  Bibra). 

HASHISCH. — In  former  times  various  hemp  preparations  were  widely  used 
as  substitutes  for  morphine.  Under  the  name  of  hashisch,  extracts  of  the  resin 
of  Indian  hemp,  Cannabis  Indica,  are  used  as  a  stimulant  throughout  the  Orient, 
especially  in  Egypt  and  in  India  as  also  in  Turkey.  The  great  instability  of 
its  active  principle,  which  has  recently  been  isolated  in  pure  form  by  8.  Frankel, 
explains  why  various  personal  experiments  which  have  been  made  in  Europe 
have  not  always  given  such  typical  results  as  would  be  expected,  judging 
by  the  descriptions  of  hashisch  intoxication  in  the  Oriental.  The  condition  of 
intoxication  produced  by  hashisch  differs  from  that  resulting  from  the  action 


42     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

of  morphine  in  the  predominance  of  pleasant  hallucinations  and  active  motor 
restlessness.  In  experiments  on  animals,  on  the  other  hand,  Frdnkel  found  that 
the  cannabinol  caused  only  narcosis  and  a  condition  of  catalepsy. 

MORPHINE  AND  SCOPOLAMINE. — The  exaggeration  of  the  effects  of 
small  doses  of  morphine  which  result  from  its  combination  with 
scopolamine  are  of  great  practical  importance.  This  synergism  may 
be  experimentally  demonstrated  in  various  species  of  animals,  espe- 
cially in  those  species  in  which  scopolamine  alone,  even  when  given 
in  large  amounts,  produces  no  narcotic  effects.  The  combined  adminis- 
tration of  small  doses  of  morphine  and  small  doses  of  scopolamine, 
which  by  themselves  produce  hardly  any  effects,  results  essentially  in 
an  exaggeration  of  the  effects  of  the  morphine  (Burgi,  Madelung). 
Morphine  and  the  hypnotics  of  the  alcohol  group  when  administered 
simultaneously  also  act  synergistically,  with  a  resulting  exaggeration 
of  each  other's  pharmacological  actions  (Burgi,  Fiihner). 

BIBLIOGRAPHY 

Alt:    Berl.  klin.  Woch.,  1889,  No.  25. 

Bergien,  W. :  Mtinchener  med.  Woch.,  1910,  No.  46. 

v.  Bibra:  Die  narkotischen  Genussmittel  u.  d.  Mensch.,  Niirnberg,  1855. 

Bouma:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  50,  p.  353. 

Burgi:  Deutsche  med.  Woch.,   1910,  No.  1. 

Faust:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  44,  p.  217. 

Flury:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  64,  p.  105. 

Hess:  Arch.  f.  wissenschaftl.  u.  prakt.  Tierheilkunde,  1901,  vol.  27. 

Hilsmann:  Dissertation,   Strassburg,    1874. 

Hitzig:  Reicherts  u.  Du  Bois'  Arch.  f.  Anat.  u.  Phys.,  1873. 

Krapelin:    Ueber  die  Beeinflussung  einfacher  psychischer  Vorglinge  durch  einige 

Arzneimittel,  Jena,  1892,  p.  225. 

Lenhartz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  22. 
Lowi,  A.:    Miinchener  med.  Woch.,  1910,  No.  46. 
Madelung:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  409. 
Marme:  Deutsche  med.  Woch.,  1883,  No.  14. 
McCrudden:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  374. 
Pringsheim:  Biochem.  Zeitschr.,   1900,  vol.  12,  p.  143. 
Riibsamen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59,  p.  227. 
Sahli,  H.:    Therapeutische  Monatshefte,  1909,  January;  Munch,  med.  Woch.,  1910, 

No.  25. 

v.  Schroder:  Arch.  f.  exp.  Path.  u.  Pharm.,   1883,  vol.   17. 
Tappeiner:   Sitzungsbericht  d.  Ges.  f.  Morph.  u.  Physiol.,  Munich,  1899. 
Tauber:   Arch.  f.  exp.  Path.  u.  Pharm.,   1890,  vol.  27,  p.  336. 
Wertheimer-Raff alowich :   Deutsche  medizinische  Wochenschrift,  1910,  No.  17. 
Witkowski:  Arch.  f.  exper.  Path.  u.  Pharm.,  1877,  vol.  7. 

ALCOHOL 

The  drugs  of  the  morphine  group,  as  we  have  learned,  exert  a 
preponderatingly  depressing  influence  on  the  central  nervous  system 
of  vertebrates  and  produce  in  invertebrates  quite  different  effects 
and  in  vegetable  organisms  no  effects  at  all. 

The  next  group  which  we  have  to  consider  is  a  large  and  quite 
different  one,  consisting  of  substances  whose  actions,  while  preponder- 
atingly depressing  ones,  are  not  confined  to  the  central  nervous  system 
of  vertebrates,  but  are  exerted  on  all  types  of  animal  organisms  and 


HYDROCARBON  HYPNOTICS  43 

affect  not  only  nervous  tissues  but  all  living  protoplasm.  This  is 
the  GROUP  OF  ALCOHOL  [spoken  of  also  by  various  authors  as  the 

ALCOHOL-CHLOROFORM   GROUP,    the  GROUP   OF   HYDROCARBON   NARCOTICS, 

etc. — TR.]  This  somewhat  arbitrarily  named  group  includes,  as  a 
matter  of  fact,  all  indifferent  organic  carbon  compounds  which  are 
soluble  in  fats,  with  the  exception  of  such  hydrocarbons  as  are  not 
volatile  and  are  entirely  insoluble  in  water,  and  are  consequently  in- 
capable of  absorption  by  the  organism.  Among  its  members  may  be 
found  simple  and  substituted  hydrocarbons,  alcohols,  aldehydes, 
ketones,  ethers,  esters,  acid  amides,  substituted  ureas,  and  other  types 
too  numerous  to  mention. 

Of  this  practically  unlimited  number  of  substances  only  a  rela- 
tively few  are  actually  employed  as  medicines,  which  are  variously 
known  as  hypnotics  or  sedatives  and  as  anaesthetics,  according  as  their 
action  is  more  or  less  pronounced  or  lasting  or  evanescent.  Ethyl 
alcohol  occupies  an  intermediate  position  between  these  two  classes, 
connecting  them  and  belonging,  as  it  were,  to  both.  Consequently  its 
properties  and  actions  should  be  discussed  first  of  all. 

ALCOHOL. — Ethyl  alcohol,  C2H5OH,  is  formed  from  sugar  by  yeast 
fermentation.  When  during  the  fermentation  about  18  per  cent, 
of  alcohol  has  been  formed,  the  fermentation  ceases,  but  may  be  started 
up  again  by  dilution  with  water.  It  is  thus  evident  that  even  yeast 
cells  are  paralyzed  by  a  certain  concentration  of  alcohol  in  the  sur- 
rounding fluid,  and  this  power  of  alcohol  to  depress  or  paralyze 
functional  activities  is  found  to  hold  good  for  all  forms  of  living 
organisms. 

SYMPTOMS  OF  STIMULATION  AFTER  ALCOHOL. — Often,  but  by  no 
means  always,  the  depressing  effect  of  a  drug  is  preceded  by  a  stimu- 
lating one,  and  it  is  desirable  to  determine  whether  or  not  this  is  also 
the  case  with  alcohol.  As  a  matter  of  fact,  in  man  the  first,  and, 
at  the  start,  the  only  noticeable  effects  produced  by  it,  are  exaggerated 
talkativeness  and  motor  restlessness,  quickened  breathing  and  pulse, 
and  flushing  of  the  face,  all  apparently  signs  of  stimulation,  which 
are  followed,  only  when  larger  amounts  are  consumed,  by  a  general 
depression  and  a  feeling  of  fatigue,  and  by  slowed  respiration  and 
circulation,  and  diminution  of  all  reflexes. 

It  has  been  demonstrated  that  the  primary  action,  responsible  for 
this  apparent  stimulation,  occurs  in  the  cerebral  hemispheres,  for  the 
less  the  cerebral  development  of  the  animal  the  slighter  are  the  appear- 
ances of  stimulation,  and,  as  Baratynsky  showed  in  frogs  and  pigeons, 
which,  though  decerebrated,  were  kept  alive  for  months,  these  do  not 
occur  at  all  if  the  cerebrum  has  been  removed. 

The  nature  of  this  excitement  or  stimulation  has  been  the  subject 
of  much  discussion.  Before  starting  in  on  such  discussion  it  is  desir- 
able that  the  SIGNIFICANCE  OF  STIMULATION  be  thoroughly  understood. 

Every  expression  of  life,  whether  conscious  or  unconscious,  is  a 


44    PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

reaction, — i.e.,  a  response  to  a  stimulus.  It  is  impossible  for  any 
change,  movement,  or  other  functional  activity  in  a  living  organism 
to  occur  spontaneously, — that  is,  without  a  sufficient  cause.  If  any 
substance  by  its  action  in  the  body  causes  a  reaction,  there  are  three 
ways  in  which  it  can  do  so.  It  may  do  this:  (1)  by  acting  itself  as 
a  direct  stimulus  (as  does  Nad  when  applied  to  nerves)  ;  (2)  by 
making  it  possible  for  other  constantly  occurring  but  ordinarily  sub- 
liminal stimuli  to  become  efficient;  or  (3)  by  bringing  it  to  pass 
that  the  discharge  of  energy  which  results  from  a  given  effective  stimu- 
lus produces  results  which  are  more  wide  reaching  or  violent  than 
usual.  The  first  we  call  DIRECT  STIMULATION,  the  others  EXALTATION 
OP  THE  EXCITABILITY.  The  first  may  be  compared  to  the  closing  of  the 
quicksilver  contact  in  an  electric  circuit,  the  second  to  the  rendering 
the  points  of  contact  more  delicate,  and  the  third  to  the  removal  from 
the  circuit  of  resistance  coils  or  the  interpolation  of  better  conductors. 
It  is  evident  that  in  the  last  two  cases,  which,  by  the  way,  usually 
cannot  be  differentiated  from  each  other,  we  are  dealing  with  an 
alteration  in  the  functional  condition  of  the  physiological  mechanism 
in  question,  which  causes  either  an  acceleration  of  the  reaction  or  a 
removal  of  inhibition. 

We  must  look  on  all  the  functional  activities  of  cells  as  resulting 
from  chemical  processes,  either  katabolie  (disintegrative)  or  anabolic 
(constructive  or  synthetic)  in  nature,  the  former  accompanied  by  a 
discharge  of  energy,  the  latter  leading  to  its  reaccumulation.  These 
reactions  in  the  cells  may  be  accelerated  by  catalyzing  agents  or 
retarded  by  inhibiting  ones,  in  a  fashion  quite  analogous  to  that  in 
which  chemical  reactions  may  be  modified  by  appropriate  agents. 
Increased  discharge  of  energy — that  is  to  say,  increased  functional 
activity,  or  STIMULATION — RESULTS  ALIKE  FROM  THE  REMOVAL  OF  IN- 
HIBITING FORCES  OR  THE  INTRODUCTION  OF  ACCELERATING  ONES. 

THE  BEMOVAL  OF  INHIBITION  is  perhaps  the  more  common  phenomenon, 
for  in  the  majority  or  perhaps  in  all  organs  the  functions  are  in  a  state  of 
balance  or  rivalry,  each  function  normally  being  limited  or  inhibited  by  an 
antagonistic  one.  The  elimination,  by  depression  or  paralysis,  of  any  function 
thus  results  in  the  initiation  or  augmentation  of  the  activity  of  the  correspond- 
ing antagonistic  one.  This  connection,  moreover,  obtains  not  only  between 
antagonistic  functions  but  also  between  those  which  produce  similar  effects 
and  which,  as  it  were,  compete  with  each  other.  For  example,  the  elimination 
of  the  cardiac  vagus  of  one  side  causes  an  augmentation  in  the  excitability  of 
that  of  the  other  side,  this  indicating  apparently  that  there  is  a  certain  com- 
petition between  the  influences  exerted  on  the  peripheral  cardio-inhibitory  organs 
by  the  vagi  of  the  two  sides  (v.  Tschermak) .  In  a  similar  fashion  centrifugal 
stimuli  compete  in  the  terminal  nervous  organs  with  chemical  stimuli  which 
act  in  the  periphery.  Thus  the  excitability  by  chemical  agents  of  the  peripheral 
dilator  mechanism  of  the  cat's  iris  is  augmented  by  section  of  the  cervical 
sympathetic,  which  is  the  ordinary  path  for  impulses  coming  from  the  centre 
to  this  organ. 

With  Goltz  and  J.  Loeb  we  attribute  to  the  cerebrum  the  functions 
of  inhibition  and  exclusion,  which  alone  render  possible  the  concen- 


ALCOHOL  45 

tration  of  the  attention  and  will  on  the  acts  of  perception  or  motion 
needed  at  the  time,  without  regard  to  all  other  centripetal  or  cen- 
trifugal processes  in  the  central  nervous  system.  It  seems  plausible, 
then,  to  assume  that  the  early  effects  of  alcoJwl  are  limited  to  a  weaken- 
ing of  this  inhibiting  function  of  the  cerebrum,  while  the  lower  por- 
tions of  the  central  nervous  system  are  not  directly  influenced  by  it. 
As  a  result  of  this  removal  of  inhibition,  we  see  the  evidence  of 
their  exaggerated  activity  in  the  tipsy  individual's  unrestrained  be- 
havior, his  loquacity,  his  tendency  to  laugh  or  weep  without  cause  or 
to  burst  into  a  tempest  of  rage.  As  in  certain  cases  of  bilateral  disease 
of  the  cortex  analogous  symptoms  occur,  it  would  appear  that  the 
above  assumption  satisfactorily  explains  such  symptoms.  In  the  same 
way  the  faulty  control  of  equilibrium  and  the  loss  of  muscle  sense  in 
intoxication  indicate  a  direct  depression  of  the  cerebellar  functions. 
However,  it  cannot  be  absolutely  denied  that  a  direct  stimulating  action 
is  exerted  by  alcohol  on  the  basal  ganglia  and  on  certain  centres  in  the 
medulla,  and  that  this  plays  an  important  part  here,  especially  in 
connection  with  the  symptoms  of  stimulation  of  the  motor  portions  of 
the  brain. 

MOTOR  EXCITEMENT. — It  is  well  known  that  symptoms  of  motor 
excitement  result  from  the  administration  of  alcohol,  and  it  is  to 
these  effects  that  it  owes  its  reputation  as  a  reviving  and  strengthen- 
ing agent,  of  which  use  is  gladly  made  in  cases  of  fatigue  or  bodily 
weakness  or  to  aid  in  the  performance  of  heavy  tasks.  It  is  only  in 
the  last  decades  that  an  exact  and  complete  proof  has  been  brought 
that  alcohol  actually  does  cause  such  motor  excitation.  W.  Lombard, 
using  Mosso  's  ergograph,  was  able  to  show  that,  when  small  quantities 
of  alcohol  were  taken,  the  power  of  performing  voluntary  muscular 
work  was  not  directly  increased,  but  the  development  of  the  feeling 
of  fatigue  was  postponed,  so  that  more  voluntary  work  was  per- 
formed by  the  muscles.  This,  however,  is  not  due  to  an  increase  in  the 
capacity  of  the  muscles,  for,  when  involuntary  muscular  contractions 
were  produced  by  peripheral  electric  stimulation,  alcohol  lessened  the 
capacity  for  muscular  work.  From  these  results  it  is  clear  that  the 
increase  in  capacity  for  work  is  central  in  its  causation  and  is  purely 
the  result  of  retardation  of  the  development  of  the  sensation  of  fatigue. 
Frey,  Krapelin1  and  his  collaborators,  and  Joteyko  have  confirmed 
these  observations,  but  Rivers  was  not  able  to  do  so.  Krapelin's3 
physiological  discussion  and  Joteyko's  very  plausible  explanation  of 
the  ergographic  records,  which  is  based  on  a  mathematical  analysis, 
both  indicate  that  a  facilitation  of  the  cerebral  motor  processes  is 
involved  in  these  results  (see  Pharmacology  of  the  Muscles,  p.  422). 

As  this  facilitation  of  the  motor  processes  can  be  brought  about  as  often 
as  wished  by  repeating  the  administration  of  small  amounts  of  alcohol,  Krapelin 
assumes  it  to  be  the  result  of  a  direct  but  very  temporary  exaltation  in  the 
excitability  of  the  motor  tracts  and  not  the  result  of  a  temporary  weakening 


46      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

of  inhibition.  However,  this  argument  is  not  convincing,  for  a  temporary  de- 
pression of  the  inhibitory  centres  by  alcohol  may  be  assumed  just  as  readily  as 
a  temporary  excitation  of  the  motor  ones,  and  therefore  it  could  just  as  well 
be  repeatedly  induced. 

Still  less  valid  is  the  opposing  view  that  the  direct  action  of  alcohol 
is  always  a  depressing  one,  and  that  the  "  stimulation "  produced  by  it  is 
only  an  apparent  one,  due  only  and  always  to  depression  of  inhibition  or  dis- 
turbance of  the  normal  balance  in  the  cerebrum,  etc.  As  a  matter  of  fact,  it  has 
been  shown  that  alcohol  does  produce  a  direct  augmentation  of  the  excitability 
in  isolated  frog's  nerves  (Hommsen,  Efron,  Breyer),  in  nerve-muscle  prepara- 
tions (Scheffer  and  others),  in  ciliated  epithelium  (Engelmann,  1868;  Breyer, 
1903),  and  also  in  plant  cells,  in  which  alcohol  accelerates  the  flow  of  plasma 
(E.  Josing).  All  of  this  being  so,  it  is  hard  to  see  why  it  should  not  cause 
similar  stimulation  of  central  nervous  organs  also.  Apparently  it  is  largely  a 
question  of  terminology,  for  the  utilization  of  current  in  an  electric  circuit  may 
be  increased  just  as  well  by  lessening  the  resistance,  by  shortening  the  circuit, 
or  by  cutting  out  a  portion  of  it,  as  by  improving  a  portion  of  the  conducting 
path,  and,  whether  the  conduction  is  improved  and  the  resistance  thus  lessened 
or  whether  the  conduction  for  a  competing  or  antagonistic  current  be  lessened, 
the  result  is  the  same,  for  it  is  always  a  question  simply  of  supplying  greater 
current  energy  through  the  excited  segment  and  not  of  the  production  of  energy. 

The  "STIMULATION"  from  a  single  dose  of  alcohol  is  never  of 
long  duration,  lasting  only  for  30  to  60  minutes,  and  with  larger 
amounts  it  is  quickly  followed  by  depression.  For  abstemious  adults 
the  limits  for  such  ' '  stimulating ' '  doses  may  be  placed  at  about  30-40 
grammes  of  alcohol,  corresponding  to  250-500  c.c.  of  wine  or  a  litre 
of  beer.  For  those  accustomed  to  the  use  of  alcohol  the  dose  must 
naturally  be  somewhat  larger. 

In  addition  to  facilitating  the  performance  of  motor  acts,  alcohol 
also,  especially  in  sickness  or  exhaustion,  when  such  may  be  accom- 
plished only  by  considerable  effort  of  the  will,  produces  a  feeling  of 
increased  strength  and  of  general  well-being.  Other  physiological 
processes,  such  as  those  of  nutrition  and  metabolism,  may  be  indirectly 
influenced  in  a  favorable  sense  by  the  improved  nervous  condition. 
In  this  way  one  phase  of  the  analeptic,  stimulating  action  of  alcohol 
is  sufficiently  explained.  Moreover,  it  is  a  well-known  fact  that 
when  alcohol  is  taken  frequently,  there  quickly  develops  a  habituation 
to  the  effects  produced  on  the  nervous  system,  so  that  the  stimulation 
felt  at  the  start  is  no  longer  experienced  unless  the  amounts  taken  are 
increased.  Consequently  it  is  clearly  evident  that  the  habitual  daily 
use  of  alcohol  is  not  only  incapable  of  facilitating  or  improving  the 
performance  of  physical  work,  but  that,  on  the  contrary  (on  account 
of  its  other  harmful  actions),  it  impairs  it.  The  experience  obtained 
in  different  wars  and  in  sports  is  in  complete  accordance  with  this 
view. 

RESPIRATION. — The  other  side  of  the  stimulating  action  of  alcohol, 
in  so  far  as  the  central  nervous  system  is  concerned,  deals  with  its 
effects  on  the  respiration.  This  is  strengthened  so  that  the  respiratory 
volume — i.e.,  the  amount  of  air  respired  in  a  unit  of  time — is  in- 
creased. This  is  due  not  only  to  REFLEX  STIMULATION  through  the 
senses  of  taste  and  smell  and  from  the  bronchial  and  stomach  nerves, 


ALCOHOL  4? 

or  to  increased  muscular  activity,  but  probably  also  to  a  DIRECT 
STIMULATION  of  the  respiratory  centre  (Wilmanns  and  others).  This 
strengthening  of  the  respiration  occurs  even  in  sleep  and  after  doses 
which  cause  sleep,  and  consequently  this  action  may  be  of  value  clini- 
cally in  cases  of  poisoning  or  shock.  However,  the  more  volatile 
members  of  the  alcohol  group  (ether,  acetic  ether,  etc.)  are  in  this 
respect  more  efficient  and  useful.  It  goes  without  saying  that  such  an 
artificial  strengthening  of  the  respiration  can  be  of  no  value  to  healthy 
hard-working  men. 

EFFECTS  ON  THE  POWERS  OF  PERCEPTION  AND  ASSOCIATION. — As 
far  as  has  been  shown  up  to  the  present,  most  of  the  functions  of  the 
central  nervous  system  are  depressed  by  alcohol.  This  is  especially 
so  for  the  faculties  of  perception  and  association.  This  is  evident 
from  the  general  experience  that  judgment  is  never  improved  by 
alcoholic  indulgence,  but  is  always  impaired,  and  the  exactly  conducted 
psychological  studies  of  Krdpelin  l>3  and  his  collaborators  led  them 
to  the  same  conclusions. 

EFFECTS  ON  THE  MOOD. — The  sensation  of  physical  and  psychical 
well-being  is  determined  by  the  intensity  of  the  feelings  of  discomfort 
and  by  the  intensity  of  the  inhibitions,  under  whose  constantly  varying 
influence  we  exist,  for  positive  feelings  of  pleasure  can  never  be  con- 
sciously experienced  except  for  the  time  being  and,  according  to  the 
law  of  Weber  and  Fechner,  must  consequently  disappear  if  the 
stimuli  remain  the  same.  The  feeling  of  health  in  a  similar  fashion 
means  nothing  else  than  the  failure  to  be  conscious  of  any  pathological 
disturbance.  From  this  it  necessarily  follows  that  any  general  blunt- 
ing of  the  perception  and  conception  of  life  must  lead  to  an  euphoria, 
and  if,  in  every-day  life,  "wine  makes  glad  the  heart  of  man,"  it  is 
self-evident  that  this  must  be  even  more  true  for  an  invalid  suffering 
in  body  and  soul.  As  a  matter  of  experience,  almost  all  the  functions 
of  the  body,  the  appetite,  and,  depending  on  it,  the  digestion,  the 
metabolism,  the  circulation,  the  respiration,  and  the  ability  to  sleep, 
are  very  markedly  affected  by  the  general  subjective  condition, — i.e., 
by  the  intensity  of  the  subjective  euphoria.  Therefore,  it  is  evident 
that,  in  proper  cases,  alcohol  may  be  a  very  valuable  medicament  for 
the  preservation  and  augmentation  of  the  strength  of  the  invalid. 

However,  it  is  important  to  emphasize  the  fact  that  in  many 
nervous  patients  any  amounts  of  alcohol,  even  very  moderate  ones, 
can  produce  harmful  effects.  This  is  the  case,  among  others,  with 
epileptics,  whose  condition  of  depression  in  many  particulars  resem- 
bles that  caused  by  alcoholic  intoxication,  and  may  be  most  strikingly 
aggravated  as  a  result  of  the  consumption  of  alcohol  (Krdpelin2). 
Moreover,  it  should  not  be  forgotten  that  grave  harm  may  result  from 
advising  long-continued  or  regular  use  of  alcohol  for  the  purpose  of 
strengthening  a  patient,  or  of  stimulating  his  appetite  and  calming 
his  nerves,  and  that,  under  all  circumstances,  this  is  particularly 


48     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

dangerous  advice  to  give  to  neurasthenic  patients  in  whom  the  will 
power  is  weak. 

Large  doses  of  alcohol  cause  blunting  and  complete  paralysis  of 
the  functional  activity  of  the  cerebrum.  The  consciousness  and  the 
cerebral  reflexes  are  abolished.  The  centres  for  the  regulation  of  heat 
and  the  spinal  centres  are  paralyzed,  and  finally,  when  fatal  doses 
have  been  given,  the  excitability  of  the  respiratory  centre  in  the-medulla 
is  completely  abolished.  Therapeutically  this  narcotic  action  of  alco- 
hol may  be  utilized  in  the  symptomatic  treatment  of  conditions  of 
excessive  excitability  of  the  reflex  centres,  as,  for  example,  in  strych- 
nine poisoning.  This  is  especially  the  case  if  other,  perhaps  more 
appropriate,  remedies  are  not  at  hand.  It  is  also  of  some  interest 
that  some  savage  races  are  accustomed  to  intoxicate  to  a  state  of 
complete  insensibility  (Felkin),  with  palm  wine  or  other  alcoholic 
beverages,  any  one  about  to  be  operated  upon,  and  under  certain  con- 
ditions this  could  be  done,  in  case  of  need,  even  in  civilized  lands. 
However,  it  is  impossible  to  estimate  beforehand,  with  any  certainty, 
the  duration  of  the  primary  stage  of  excitement  or  that  of  the  complete 
narcosis  with  abolition  of  the  reflexes.  In  addition  to  this  decided 
disadvantage,  the  use  of  alcohol  as  an  anaesthetic  possesses  also  the 
disadvantage  that  it  is  followed  by  long-continued  extremely  dis- 
agreeable after  effects.* 

CIRCULATION. — Inasmuch  as  alcohol,  as  has  already  been  men- 
tioned, exerts  its  action  not  only  on  the  nervous  tissues  but  also 
on  all  living  protoplasm,  in  man  its  effects  are  not  limited  to  those 
on  the  functions  of  the  central  nervous  system,  but  are  exerted  with 
greater  or  lesser  intensity  on  the  functions  of  all  organs.  At  this 
time  these  will  be  discussed  only  in  so  far  as  appears  necessary  to 
secure  a  proper  understanding  of  its  greatest  action.  A  part  of  this 
is  a  strengthening  of  the  cardiac  action  and  an  acceleration  of  the 
pulse,  which  in  health  occurs  to  but  a  slight  degree  or  not  at  all,  but 
which  in  disease  is  often  manifested  in  a  very  useful  and  striking 
fashion  (see  pp.  258,  316). 

Alcohol  also  depresses  the  tone  of  the  vasomotor  centres  and  thus 
dilates  the  vessels,  particularly  the  cutaneous  ones.  The  FEELING  OP 
WARMTH,  which  is  obtained  by  drinking  alcohol  when  cold,  depends  on 
this  dilatation  of  these- vessels,  for  our  sensations  of  warmth  depend 
entirely  on  the  condition  of  the  terminal  organs  of  the  cutaneous  tem- 
perature nerves.  That  is  to  say,  the  better  the  circulation  in  the  skin 
the  warmer  we  feel.  Consequently,  even  small  doses  of  alcohol,  as  a 
result  of  this  dilation  of  the  cutaneous  vessels,  produce  a  deceptive 

*  According  to  FinJcelnburg,  alcohol  causes  a  rather  lasting  stimulation  of 
the  secretion  of  the  liquor  cerebri  and  consequently  an  increase  in  the  sub- 
arachnoid  pressure.  It  is  not  impossible  that  the  post-alcoholic  headache  is  due 
to  this  increase  in  intracranial  pressure  [for  spinal  puncture  can  often  bring 
prompt  and  striking  relief. — TB.]. 


ALCOHOL  49 

feeling  of  warmth,  in  spite  of  the  fact  that  larger  amounts  of  heat  are 
lost  by  the  body  as  a  result  of  bringing  heat  from  the  interior  of  the 
body  to  the  surface  where  it  is  given  off. 

After  non-narcotic  doses  this  greater  LOSS  OP  HEAT  is  not  compen- 
sated for  by  an  increase  in  the  production  of  heat,  for  after  large 
doses  the  heat-regulating  nerves,  like  the  other  cerebral  centres,  are 
depressed  and  the  regulation  by  chemical  means  becomes  inadequate, 
and  consequently  the  temperature  of  the  body  is  markedly  lowered.  This 
is  an  explanation  of  the  danger  of  an  intoxicated  individual's  freezing 
to  death  in  winter.  As  will  be  more  fully  discussed  in  the  section  on 
antipyresis,  the  disturbance  of  the  heat-regulating  mechanism  is  espe- 
cially pronounced  in  fever,  and  in  former  times  alcohol  was  used  as 
an  antipyretic.  As  a  matter  of  fact,  its  thermic  action  is  in  principle 
not  at  all  different  from  that  of  the  true  antipyretics,  but  it  is  devel- 
oped only  after  doses  which  produce  marked  effects  on  other  functions. 
Consequently,  alcohol  should  not  be  used  as  a  specific  antipyretic, 
any  more  than  arsenic  should  be  used  as  an  emetic  although  its  emetic 
action  is  entirely  similar  to  that  of  antimony. 

ANTISEPTIC  ACTION. — As  a  result  of  certain  clinical  observations, 
the  claim  has  been  made  that  alcohol  can  exert  antiseptic  and  bacteri- 
cidal actions  after  it  has  been  absorbed  into  the  blood ;  but  this  assump- 
tion has  no  valid  foundation.  As  far  as  it  is  possible  to  draw  any 
conclusions  from  the  experimental  observations  of  Laitinen,  it,  on  the 
contrary,  diminishes  the  resistance  to  bacterial  infection.  That,  how- 
ever, patients  with  septic  fever  can  support  very  unusually  large 
amounts  of  alcohol  without  becoming  intoxicated  is  a  noteworthy  fact, 
which  has  been  observed,  and  which  may  be  explained  in  the  same 
way  as  the  unusually  high  resistance  to  morphine  exhibited  by  dogs 
poisoned  by  atropine  (Binz}.  It  is  also  possible  that  in  fever  alcohol 
is  combusted  more  rapidly  than  in  health,  but  thus  far  this  has  not 
been  investigated. 

Externally,  however,  on  account  of  its  solubility  in  fat  and  water, 
and  on  account  of  its  power  of  hardening  the  tissues,  alcohol  may  be 
advantageously  used  as  a  disinfectant  (Ahlfeld).  On  account  of 
these  same  properties,  when  alcohol  is  rubbed  on  the  skin  it  penetrates 
the  epithelium  and  causes  a  local  irritation  of  sensory  and  vasodilator 
nerve-endings  and  may  be  used  as  a  counterirritant. 

THE  FATE  OP  ALCOHOL  IN  THE  BODY. — Alcohol,  with  the  exception 
of  slight  traces  (2-5  per  cent.)  which  leave  the  body  through  the 
lungs,  is  completely  burned  in  the  bodies  of  warm-blooded  animals, 
self-evidently  with  a  corresponding  production  of  heat.  According 
to  Pringsheim,  animals  accustomed  to  alcohol  combust  it  more  rapidly 
than  the  unhabituated  controls,  its  combustion  taking  place  in  about 
two-thirds  of  the  time  which  is  necessary  for  the  combustion  of  similar 
doses  when  administered  to  the  controls. 

It  has  been  established  by  numerous  investigators  ( Atwater,  R.  0. 

4 


50     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

Neumann,    Rosemann,    and    others)    that    CALORICALLY    EQUIVALENT 

AMOUNTS  OF  THE  CARBOHYDRATES  AND  PATS  OP  THE  BODY  MAY  BE  PRO- 
TECTED PROM  COMBUSTION  BY  THE  METABOLIC  COMBUSTION  OP  ALCOHOL. 

Under  certain  circumstances  it  appears  to  be  able  to  act  as  a  physio- 
logical substitute  for  the  carbohydrates,  aside  from  the  utilization  of 
its  caloric  energy  value,  a  fact  which  appears  not  without  importance. 
In  diabetic  acidosis  the  administration  of  alcohol,  like  that  of  carbo- 
hydrates, decreases  the  formation  of  acetone  (tfeubauer)  [and  also 
that  of  the  pathologically  more  important  oxybutyric  acid. — TR.]. 
Alcohol  may  therefore,  in  so  far  as  its  toxic  side  actions  may  be  disre- 
garded, be  considered  as  a  surrogate  for  food,  and  may  occasionally 
be  useful  as  such  in  the  treatment  of  disease. 

BIBLIOGRAPHY 

Ahlfeld:  Volkmann's  Samml.  klin.  Vortr.,  Nos.  310,  311,  1901. 

Baratynsky:   Arch,  des  science  biol.  St.  Petersbourg,   1894,  vol.  3,  p.  167. 

Binz:   Zbl.  f.  klin.  Med.,   1893,  vol.   14. 

Breyer:  Pfliiger's  Arch.,  1903,  vol.  99,  p.  481. 

Efron:   Pfliiger's  Arch.,  1885,  vol.  36,  p.  467. 

Felkin:    Lage  und  Stellung  der  Frau  bei  der  Geburt.,  Dissert.  Marburg,  1885. 

Finkelnburg:  D.  Arch.  f.  klin.  Med.,  1904,  vol.  80. 

Frey:  Mitt,  aus  Klin.  d.  Schwei/.,  Series  4,  1896,  vol.  1. 

Fuhner:  Miinchn.  med.  Woch.,  1911,  No.  4. 

Josing,  E.:  Jahrb.  f.  w.  Botanik.,  1901,  vol.  36. 

Joteyko:    Trav.  du  labor,  de  1'inst.  Solvay,  Bruxelles,  1904,  No.  6,  p.  4. 

1  Krapelin :  Ueber    d.    Beeinflussung    einf    psychischer    Vorgange    durch    einige 

Arzneimittel,  Jena,  1892. 

2 Krapelin:  Miinchn.  med.  Woch.,  1899,  No.  42. 
3  Hoch   u.   Krapelin,   Psychol.   Arbeiten,    1895. 

Laitinen:   Ztschr.  f.  Hygiene  u.  Infektionskrankh.,  1900,  vol.  34,  No.  2. 
Lombard,  Warren:  Journ.  of  Physiol.,   1892,   13. 
Mommsen:  Virchow's  Arch.,  1881,  vol.  83,  p.  243. 
Neubauer:  Miinchner  med.   Woch.,   1906,   No.    17. 
Neumann,  R.  O.:    Arch.  f.  Hygiene,  1899,  vol.  36;  Miinchn.  med.  Woch.,  1901r 

No.  28. 

Pringsheim:  Biochemische  Zeitschr.,  1908,  vol.  12. 

Rivers:  The  Infl.  of  Alcohol  and  other  Drugs  on  Fatigue,  London,  1908. 
Scheffer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  44,  p.  24. 
v.  Tschermak:  Monatshefte  f.  Psych,  u.  Nerol.,  1909,  vol.  26. 
Wilmanns:  Pfluger's  Arch.,  1897,  vol.  66,  p.  167. 

GENERAL  ANESTHETICS 

While  studying  the  action  of  alcohol  on  the  central  nervous 
system,  we  have  at  the  same  time  been  learning  the  typical  effects  of 
a  very  large  number  of  other  substances,  of  which  the  greater  number 
belong  to  the  aliphatic  series.  These  are  those  hydrocarbons,  alcohols, 
ethers,  esters,  etc.,  of  an  indifferent  nature,  possessing  neither  acid  nor 
alkaline  properties,  nor  those  of  the  salts,  and  which  are  characterized 
less  by  their  chemical  than  by  their  physical  affinity  for  certain  con- 
stituents of  the  protoplasm.  Some  other  substances  which  do  not  be- 
long to  the  aliphatic  series — as,  for  example,  nitrous  oxide  or  carbon 
dioxide — also  are  to  be  considered  as  belonging  pharmacologically 
to  this  great  alcohol  group.  Naturally,  though,  of  all  this  large  army 


GENERAL  ANAESTHETICS  51 

of  substances,  only  a  few  are  practically  useful  in  medicine, — namely, 
those  whose  narcotic  action  is  relatively  a  pure  one  and  at  the  same 
time  sufficiently  powerful. 

However  different,  on  superficial  observation,  may  be  the  appear- 
ance of  an  ether  narcosis,  which  is  well  developed  but  which  lasts 
but  a  short  time,  from  that  of  the  merely  calming  but  rather  persistent 
effect  of  a  small  dose  of  sulphonal,  in  their  nature  the  actions  of  these 
drugs  are  essentially  similar,  but  in  the  two  cases  we  utilize  entirely 
different  degrees  or  phases  of  an  action  which  in  principle  is  identical. 
In  each  case  these  substances,  whether  classed  as  hypnotics  or  anaes- 
thetics, when  given  in  large  doses,  by  their  depressing  action  abolish, 
for  the  time  being,  the  functions  of  the  brain  and  also  those  of  the 
spinal  cord,  while  the  respiratory  centre  is  still  able  to  perform  its 
functions  satisfactorily  and  the  circulation  remains  comparatively 
little  affected.  In  anaesthesia  produced  by  ether  or  chloroform,  the 
fact  that  they  are  administered  through  the  lungs  makes  it  possible 
very  accurately  to  induce  that  degree  of  their  pharmacological  action 
which  is  just  this  side  of  the  danger  line,  and  to  maintain  this  con- 
dition only  as  long  as  appears  necessary  for  the  painless  accomplish- 
ment of  the  operation.  In  contradistinction  to  this,  when  hypnotics 
are  used,  it  is  only  the  early  stage  of  the  general  "alcohol"  action 
which  is  utilized,  during  which  stage  the  excitability  of  certain  func- 
tional tracts  in  the  cerebral  cortex  is  depressed  only  to  a  slight  degree. 

HISTORICAL. — Medicine  owes  the  discovery  of  general  anaesthesia 
to  experiments  which  were  made  to  determine  the  effects  of  chemically 
pure  gases  on  human  beings.  When,  -toward  the  end  of  the  eighteenth 
century,  the  science  of  chemistry  was  occupying  itself  with  various 
gaseous  substances,  the  effects  of  these  gases  in  human  beings  was 
frequently  studied,  and  in  fact  the  attempt  was  made  to  utilize  these 
effects  in  the  treatment  of  disease.  The  intoxicating  effects  of  nitrous 
oxide  were  discovered  early  in  the  nineteenth  century  by  the  English 
physicist,  Humphry  Davy,  who  recognized  that  ' '  among  other  proper- 
ties nitrous  oxide  appears  to  possess  the  power  of  relieving  pain/" 
and  he  suggested  that  it  could  be  advantageously  used  for  surgical 
operations.  However,  the  fact  that  the  condition  of  intoxication 
observed  was  merely  a  forerunner  of  a  true  narcosis  was  not  recognized 
by  Davy  or  his  contemporaries,  perhaps  because  of  the  difficulty  of 
handling  the  gas. 

Consequently  experiments  with  the  inhalation  of  nitrous  oxide  went 
out  of  fashion,  and  were  only  now  and  then  conducted  for  the  pur- 
pose of  demonstration,  in  spite  of  the  fact  that  at  the  start  they  had 
been  described  with  great  enthusiasm  and  had  been  frequently  re- 
peated. It  was  due  to  such  a  demonstration  in  Hartford,  Conn.,  that 
the  dentist,  H.  Wells,  in  1844,  forty  years  after  Davy's  discovery, 
rediscovered  nitrous  oxide  anaesthesia. 


52     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

He  noticed  that  one  of  the  persons  to  whom  this  gas  had  been  administered, 
after  inhaling  it  staggered  about  in  a  somewhat  intoxicated  condition,  and  hap- 
pening, while  so  doing,  to  receive  a  by  no  means  slight  injury,  exhibited  no  signs 
of  suffering.  Wells,  however,  did  not  succeed  in  introducing  nitrous  oxide 
anaesthesia  into  practice,  his  endeavors  to  do  so  remaining  fruitless  on  account 
of  the  difficulty  with  which  the  gas  could  be  handled  and  because  it  was  not 
suitable  for  major  operations.  It  was  only  at  a  much  later  date  that  an  improved 
technic  permitted  this  method  of  anaesthesia  to  be  widely  adopted. 

However,  the  idea  of  inducing  anaesthesia  by  causing  a  gas  to  be  inhaled 
was  pursued  further,  with  happier  results,  by  an  eye-witness  of  Wells's  earlier 
experiment,  Morton,  a  Boston  dentist,  who  in  cooperation  with  the  chemist, 
Jackson,  sought  for  some  gas  more  suitable  for  this  purpose.  Jackson  suggested 
that  experiments  be  made  with  ether,  whose  intoxicating  effects  on  human  beings 
were  already  known,  and  which  possibly  some  surgeons  may  have  employed  even 
before  this  time. 

In  1846  in  the  Massachusetts  General  Hospital  of  Boston,  Morton 
and  the  surgeon,  Warren,  performed  the  first  major  operation  under 
ether.  This  discovery  was  communicated  to  the  Academy  in  Paris 
in  1847,  and  in  the  same  year  Flourens  also  made  the  communication 
to  the  Academy,  that,  in  experiments  on  animals,  chloroform  pro- 
duced the  same  effect  as  ether,  except  that  it  anaesthetized  them  more 
deeply  and  more  rapidly.  In  1847  Simpson  of  Edinburgh  made  use 
of  chloroform  anaesthesia  in  human  beings  for  the  first  time. 

This  most  important  step  of  progress  was  entirely  due  to  the  dis- 
covery of  volatile  narcotic  substances,  for  no  other  path  of  absorption 
is  so  adapted  for  the  rapid  attainment,  without  danger  to  life,  of  that 
degree  of  pharmacological  action  adequate  to  produce  anaesthesia,  and 
at  the  same  time  so  adapted  to  facilitate  its  rapid  diminution  at  any 
chosen  moment,  as  is  the  path  of  absorption  through  the  lungs.  All 
the  narcotics  administered  by  the  stomach  which  had  formerly  been 
used  for  the  induction  of  surgical  anaesthesia  (mandrake,  opium,  and 
alcohol)  suffer  from  the  disadvantage  that  their  actions  develop  far 
more  slowly  and  possess  the  even  greater  drawback  that,  when  once 
the  dose  had  been  administered,  one  is  entirely  unable  to  prevent  a 
further  rise  in  the  concentration  of  the  drug  in  the  blood  if  this  be 
undesirable. 

VOLATILITY  OF  PRIME  IMPORTANCE  FOR  THE  PRACTICAL  USE  OF 
GENERAL  ANAESTHETICS. — For  the  rapid  attainment  of  a  complete 
anaesthesia,  the  most  rapid  path  of  absorption  of  the  narcotic  must  be 
available,  and  it  is  equally  important  that  its  excretion  shall  also  take 
place  by  an  equally  rapid  route,  in  order  that  its  concentration  in  the 
blood  may  at  any  time  be  altered  as  occasion  arises.  When  ether  and 
chloroform  are  used  as  anaesthetics,  the  interruption  of  its  inhalation 
suffices  immediately  to  transform  the  portal  of  entry  for  the  narcotic 
into  a  most  efficient  organ  of  excretion. 

The  surprising  rapidity  with  which  volatile  substances  are  absorbed 
from  the  lungs  into  the  blood  and  pass  out  of  the  blood  into  the 
expired  air  is  readily  explained  by  the  nature  of  the  mechanism  of 
the  absorption  of  oxygen  and  excretion  of  C02  in  the  lungs,  The 


ANESTHESIA  53 

enormous  surface  of  the  pulmonary  capillaries,  from  which  the  alveolar 
air  is  separated  by  a  membrane  composed  of  only  one  layer  of  cells, 
supplies  all  the  conditions  for  the  most  rapid  interchange  of  gases 
and  vapors.  However,  this  path  is  not  available  for  all  gases,  for 
such  vapors  as  chlorine  or  sulphurous  acid,  by  their  irritating  effects, 
produce  a  spasm  of  the  glottis  and  other  reflexes  in  the  upper  air- 
passages  so  that  the  lungs  are  protected  from  them.  Consequently, 
only  such  gases  or  vapors  may  be  used  as  anaesthetics  as  are  relatively 
non-irritating  and  consequently  do  not  cause  such  defensive  reactions 
to  too  great  an  extent,  although  they  are  clearly  produced  with  a 
certain  degree  of  intensity  by  chloroform  and  especially  by  ether. 

GENERAL  ANAESTHESIA 

Among  the  narcotic  gases  and  vapors  which  may  be  inhaled  and 
which  meet  the  conditions  necessary  for  their  absorption  through  the 
lungs,  ether  and  chloroform,  and,  especially  for  short  operations,  ethyl 
bromide,  ethyl  chloride,  and  nitrous  oxide,  are  practically  the  only 
ones  which  need  be  considered.  When  properly  administered,  these 
all  produce  a  condition  of  complete  insensibility  and  unconsciousness, 
— a  general  anaesthesia.  The  term,  "general  anaesthesia,"  is  used  for 
this  condition  in  contradistinction  to  that  of  local  anaesthesia,  in 
which  the  abolition  of  sensibility  is  obtained  by  the  paralysis  of  the 
sensory  nerve-endings  at  the  seat  of  the  operation. 

In  the  induction  of  anaesthesia,  before  complete  anaesthesia  is  in- 
duced the  perception  of  impressions  from  without  is  abolished,  so  that, 
even  at  the  time  when  consciousness  is  still  preserved  and  is  only 
somewhat  clouded,  painful  procedures  are  hardly  perceived  at  all,  a 
condition  of  analgesia  having  been  attained.  When  nitrous  oxide 
anaesthesia  is  employed,  as  a  rule,  one  does  not  go  beyond  this  stage. 
In  deep  ether  or  chloroform  anaesthesia,  on  the  other  hand,  the  con- 
sciousness is  completely  abolished  and  voluntary  motions  cease,  just 
as  in  profound  sleep.  Under  these  conditions  the  lower  portions  of  the 
cerebrum,  the  basal  ganglia,  etc.,  are  put  out  of  function,  as  it  were, 
and  later  the  spinal  cord  is  similarly  affected,  so  that  the  tone  of  the 
voluntary  muscles  is  abolished  and  the  operation  is  not  disturbed  by 
any  reflex  movements.  Only  respiration,  circulation,  the  interchange 
of  gases  in  the  lungs,  and  the  metabolism  of  the  tissues  remain  approxi- 
mately normal  during  the  anaesthesia.  The  art  of  anaesthetization 
consists  largely  in  preventing  the  extension  of  such  effects  to  the 
respiratory  and  circulatory  centres. 

ETHER  (diethyl  ether,  C2H5OC2H5),  also  called  sulphuric  ether, 
on  account  of  its  manufacture  by  heating  alcohol  with  sulphuric  acid, 
is  a  clear,  colorless  fluid,  with  a  peculiar  smell  and  burning  taste, 
which  boils  at  35°  C.  [U.S.P.  36-37°  C.].  This  low  boiling  point  is 
of  great  importance,  for  it  is  the  expression  of  its  great  volatility,  which 
is  of  the  greatest  importance  for  its  administration  as  an  anaesthetic. 


54      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

At  ordinary  temperatures  the  evaporation  of  ether  occurs  rapidly  and 
is  accompanied  by  well-marked  loss  of  heat,  so  that  it  may  produce  a 
cooling  to  temperatures  far  below  0°  C. 

Ether  is  miscible  with  oils  and  alcohols  in  any  proportions,  and  is 
soluble  in  water  in  the  proportion  of  one  part  in  12  at  17°  C.,  while 
one  part  of  water  is  soluble  in  35  parts  of  ether.  Contamination  of 
ether  by  water  or  alcohol  changes  its  boiling  point  and  specific  gravity 
[0.725-0.728  U.S.P.]  and  can  consequently  be  readily  recognized. 
Among  other  tests  for  purity  prescribed  by  the  pharmacopoeia  are, 
that  it  should  not  color  litmus  paper  nor  be  colored  within  an  hour 
with  a  solution  of  potassium  hydrate.  Ether  which  is  to  be  used  for 
anaesthesia  should  be  shielded  from  light  and  should  be  kept  in  tightly 
stoppered  containers,  as  it  is  itself  very  inflammable  and,  as  a  mixture 
of  ether  and  air  explodes  with  great  violence,  ether  narcosis  should 
not  be  conducted  in  the  presence  of  unprotected  flames. 

Local  Irritant  Action. — Ether  vapor,  being  very  volatile,  has  a 
high  vapor  tension,  even  when  it  is  dissolved  in  the  body  fluids,  and 
consequently  it  penetrates  the  tissues  with  extreme  ease,  irritating, 
at  the  point  of  application,  susceptible  tissue  elements,  particularly 
the  nerve-fibres  and  the  vessel  walls.  When  ether  thus  penetrates  the  tis- 
sues, the  sensory  nerve-endings  are  first  intensely  irritated  for  a  short 
time,  then  their  sensibility  is  depressed.  These  effects  in  the  nerve- 
endings,  combined  with  the  cold  produced  by  its  evaporation,  account 
for  the  local  anaesthesia  of  the  skin  which  may  be  produced  by  this 
drug,  in  which  connection  this  action  will  be  further  discussed  (p.  118). 

The  local  irritation  of  the  sensory  nerve-endings  also  explains  cer- 
tain indirect  effects  on  the  central  nervous  system,  for  a  certain  por- 
tion of  the  effects  produced  by  ether  on  the  respiratory  and  circulatory 
centres  is  certainly  due  to  reflexes  caused  by  such  sensory  irritation. 

The  action  of  ether  after  absorption  into  the  blood  is  almost  exclu- 
sively exerted  on  the  central  nervous  system,  for,  even  when  the 
paralysis  of  most  of  the  functions  of  the  central  nervous  system  is 
well  developed,  the  circulation  is  but  little  affected,  ether  behaving 
in  this  respect  like  alcohol.  In  general  terms,  the  action  of  ether  may 
be  characterized  as  an  ''alcohol  action/'  which  is  concentrated  in  a 
short  period  of  time  and  which  is  very  pronounced.  The  chief  differ- 
ence is  that,  on  account  of  the  rapid  absorption  of  ether,  especially 
when  it  is  inhaled,  the  earlier  stages  of  the  effects  on  the  cerebrum 
are  less  prominent  than  is  ordinarily  the  case  in  alcoholic  intoxication. 
However,  in  the  first  stage  of  the  action  of  ether,  we  find  the  same 
peculiar  mixture  of  depression  of  some  functions  of  the  cerebrum 
and  of  motor  excitation  which  has  been  described  in  the  analysis  of 
the  action  of  alcohol.  In  the  second  stage  of  the  action  of  ether,  the 
anaesthesia  is  completely  developed,  just  as  is  the  case  in  very  pro- 
found alcoholic  intoxication,  with  depression  of  all  the  cerebral  func- 
tions and  also  of  the  spinal  reflex  mechanisms,  the  centres  in  the 


ETHER,  CHLOROFORM  55 

medulla  being  the  last  to  be  affected  and  the  heart  beating  relatively 
well  even  when  death  results  from  cessation  of  the  respiration. 

Excretion. — Ether  is  excreted  in  the  expired  air,  by  far  the  largest 
portion  leaving  the  body  very  rapidly. 

As  the  effects  of  ether  on  the  central  nervous  system  in  general 
agree  with  those  of  chloroform,  these  two  drugs  can  well  be  considered 
and  discussed  together. 

CHLOROFORM,  trichlormethane,  CHC13,  is  a  clear,  colorless  fluid, 
boiling  at  62°  C.,  the  vapor  having  a  sweetish  odor  and  taste.  It.  is 
very  slightly  soluble  in  water  (about  1 :  200),  but  miscible  with  alcohol, 
ether,  and  the  fatty  oils  in  any  proportion.  In  contradistinction  to 
that  of  ether,  chloroform  vapor  is  neither  inflammable  nor  explosive. 
However,  the  ansesthetization  with  chloroform  in  the  presence  of  gas- 
lights is  attended  with  certain  disadvantages,  as,  in  the  combustion 
of  its  vapor,  the  gas,  phosgen,  CC120,  and  hydrochloric  acid  are  formed, 
both  of  which  are  very  irritant  to  the  mucous  membranes  (Gerlinger). 

Properties. — As  chloroform  decomposes  readily  under  the  influence  of  light 
and  air,  it  should  be  kept  in  opaque  and  completely  filled  containers.  As  the 
addition  of  a  small  amount  of  alcohol  renders  it  more  stable,  the  pharmaco- 
poeia permits  it  to  contain  0.6-1  per  cent,  of  alcohol. 

Liebig  and  Houbeyran  prepared  chloroform  for  the  first  time  at  about 
the  same  time, — the  former  by  allowing  KOH  to  act  upon  chloral,  and  the  latter 
by  distilling  alcohol  with  chlorinated  lime;  the  latter  method  of  preparation 
being  the  one  which  is  more  generally  used.  If  impure  alcohol  is  used  in  its 
manufacture,  an  impure  product  is  obtained  which  must  be  purified.  A  com- 
pletely pure  chloroform  may  be  obtained  from  chloral  by  decomposing  it  with 
soda,  while  other  pure  forms  may  be  obtained  by  distilling  acetone  with  chlo- 
rinated lime  or  by  crystallizing  chloroform  by  cooling  to  — 70  to  — 80°  C., 
or  from  its  crystalline  compound  with  salicylic  acid  anhydride.  However,  these 
absolutely  pure  chloroforms  possess  no  advantages  for  medicinal  purposes  over 
the  chloroform  of  the  pharmacopoeia,  which  has  a  specific  gravity  of  1.490. 

The  Pharmacopoeial  tests  for  the  detection  of  impurities  are  reliable  and 
give  a  guaranty  of  its  purity  quite  sufficient  for  its  employment  by  physicians. 
[If  some  chloroform  be  allowed  to  evaporate  in  a  watch-glass,  the  last  drop  should 
have  an  irritant  effect  when  inhaled.  Distilled  water  shaken  up  with  chloroform 
should  give  no  reaction  with  potassium  iodide  and  starch,  nor  with  silver  nitrate, 
nor  should  such  water  redden  litmus  paper.  When  left  in  contact  with  concen- 
trated sulphuric  acid,  chloroform  should  not  be  darkened  in  color  in  less  than 
one  hour. — TR.] 

Local  Irritant  Action. — In  equal  concentration  chloroform  is  far 
more  irritant  to  the  tissues  than  is  ether.  When  applied  to  the  exter- 
nal skin,  it  causes  first  a  feeling  of  coolness  due  to  evaporation,  then 
burning  and  reddening.  If  its  evaporation  is  prevented,  it  may  cause 
active  inflammation  and  the  formation  of  blisters.  Dissolved  in  oil  it 
produces  a  less  intense  but  more  lasting  irritation  of  the  skin.  Its 
local  irritant  effects  are  even  more  pronounced  on  the  mucous  mem- 
branes, so  that,  when  poisoning  has  resulted  from  swallowing  chloro- 
form, serious  lesions  of  the  stomach  and  bloody  vomiting  and  diarrhoea 
result. 

Excretion. — Much  the  larger  portion  of  the  chloroform  is  excreted 
through  the  lungs  and  with  great  rapidity,  but  a  small  portion  is 


56     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

decomposed  in  the  body,  and  as  a  result  the  chlorides  in  the  urine 
are  increased  (Zeller). 

The  narcotic  action  of  chloroform,  as  also  that  of  ether,  is  a  very 
general  one.  Wherever  in  the  organic  world  sensory  and  motor  phe- 
nomena are  to  be  found,  these  expressions  of  life  are  abolished  if  these 
anaesthetics  are  applied  in  sufficient  concentration.  The  alterations 
in  cell  functions  caused  by  them  may  be  best  observed  if  motor 
phenomena  occur  as  a  visible  expression  of  cell  life.  In  plants  they 
abolish  the  movement  of  the  protoplasm.  The  experiments  on  the 
sensitive  plant,  Mimosa  pudica,  the  irritability  of  which  is,  for  the 
time  being,  abolished  by  the  action  of  anaesthetics,  is  a  striking  demon- 
stration of  such  action  (Dutrochet,  Leclerc,  P.  Bert)  (for  further 
literature  on  the  action  of  narcotics  on  plants  see  0.  Richter) .  Their 
influence  on  motor  phenomena  in  animal  cells  may  be  very  simply 
demonstrated  on  ciliated  epithelium,  the  ciliary  movements  of  the 
epithelium  in  the  mucous  membrane  of  the  posterior  portion  of  the 
frog's  throat  being  no  longer  able  to  move  a  small  particle  placed 
on  its  surface  if  it  be  exposed  to  an  anaesthetic  gas. 

With  a  more  pronounced  degree  of  toxic  action,  death  ensues  in 
the  cells  of  all  tissues,  the  red  blood-cells  are  destroyed  by  stronger 
concentrations,  and  rigor  of  the  muscles  ensues  (Kussmaul)  and  the 
peripheral  nerves  are  rendered  unexcitable  (/.  Bernstein) .  However, 
all  such  effects,  which  may  be  produced  by  anaesthetics  on  the  blood, 
the  muscles,  and  the  peripheral  nerves  outside  of  the  body,  are  of  no 
significance  in  connection  with  the  use  of  the  anaesthetics  in  medicine, 
for  the  central  nervous  system  and  also  the  heart  are  so  much  more 
susceptible  that  death  occurs  as  a  result  of  paralysis  of  the  respira- 
tion and  the  heart  long  before  these  cells  are  affected.  [Some  destruc- 
tion of  the  red  cells  does,  however,  occur  during  ordinary  anaesthesia, 
particularly  if  this  be  prolonged  or  is  very  deep. — TR.].  It  is  owing 
to  this  much  greater  susceptibility  of  the  nervous  system  that  ances- 
thetics,  which  are  fundamentally  toxic  to  all  living  cells,  may  be, 
employed  to- influence  solely  the  functions  of  perception  and  action. 
They  may  be  used  as  anaesthetics  primarily  because  they  depress  first 
the  cerebrum  and  then  the  spinal  reflex  centres,  while  the  respiratory 
centre  resists  their  paralytic  action  longer  than  all  other  portions  of 
the  central  nervous  system. 

CLINICAL  PICTURE  OF  GENERAL  ANAESTHESIA. — At  the  commence- 
ment of  the  anaesthesia  a  condition  resembling  intoxication  develops, 
during  which  the  consciousness  is  clouded  and  is  occupied  by  confused 
ideas.  At  this  time  there  is  more  or  less  well-developed  motor  rest- 
lessness, and  consequently  this  is  often  spoken  of  as  the  stage  of  excite- 
ment. Loud  and  foolish  talking,  laughing,  etc.,  and  active  movements 
may  occur,  the  face  being  reddened  and  the  pupils  dilated.  While 
these  symptoms  of  excitement  are  in  many  cases,  particularly  in 
women  and  children,  but  little  developed  and  pass  off  rapidly,  in 


GENERAL  ANESTHESIA  57 

men,  and  especially  in  potators,  they  may  be  so  marked  as  to  resemble 
delirium  of  maniacal  attacks.  The  more  rapidly  the  concentration  of 
the  anaesthetic  in  the  blood  increases,  the  more  rapidly  does  this  stage 
pass  over  into  that  of  complete  unconsciousness.  When  this  develops, 
the  eyes  assume  the  same  position  as  in  normal  sleep,  being  turned 
inward  and  upward  and  the  pupils  being  somewhat  contracted.  The 
sensibility  is  already  abolished,  although  the  reflexes  still  exist  at  this 
stage,  and,  in  fact,  even  earlier,  at  a  time  when  the  sense  of  touch  is 
but  slightly  impaired  and  when  the  patient  may  still  be  awakened  by 
shouting  and  shaking,  analgesia  is  already  present.  This  analgesia, 
developing  before  complete  abolition  of  the  consciousness,  may  be 
utilized  for  the  performance  of  many  minor  operations. 

Some  time  after  the  complete  abolition  of  the  cerebral  functions 
the  reflex  centres  in  the  cord  become  paralyzed,  and  with  the  disap- 
pearance of  the  reflexes  the  muscle  tone  is  also  abolished,  so  that  the 
anesthetized  patient  lies  completely  relaxed,  motionless,  and  without 
sensation.  A  stage,  named  by  some  the  stage  of  toleration,  by  others 
the  stage  of  surgical  anaesthesia,  has  now  been  reached.  Among  the 
reflexes  the  last  to  disappear  is  the  corneal  reflex,  whose  disappear- 
ance, as  is  well  known,  is  the  signal  for  the  surgeon  that  the  further 
administration  of  the  anaesthetic  should  be  limited.  Even  in  complete 
anaesthesia  the  pupils  should  remain  contracted,  their  gradual  dilata- 
tion indicating  an  insufficient  respiration,  while  their  sudden  dilatation 
is  a  sign  of  imminent  danger  to  life.  [As  the  pupils  also  dilate  during 
recovery  from  the  anaesthetic,  their  dilatation  may  also  be  an  indica- 
tion of  this.— TR.] 

As  a  rule,  in  chloroform  anaesthesia  the  pulse  is  but  slightly  slowed, 
and  after  a  time  the  face  becomes  pale.  Marked  retardation  of  the 
pulse  to  50  beats  or  less  per  minute  and  extreme  pallor  are  signs  of 
a  dangerous  impairment  of  the  circulation.  In  ether  anaesthesia,  on 
the  contrary,  the  face  remains  flushed  and  the  pulse  is  usually  some- 
what accelerated.  [If  before  operation  the  pulse  has  been  abnormally 
rapid,  it  very  frequently  is  distinctly  slowed  and  strengthened. — TR.] 
In  complete  anaesthesia  with  ether  or  chloroform  the  respiration 
should  be  somewhat  slowed,  but  should  be  regular  and  sufficiently 
deep. 

INFLUENCE  ON  MOTOR  AND  SENSORY  FUNCTIONS. — The  mere  surface 
picture  of  anaesthesia  shows  that  the  sensibility  of  the  cerebral  cortex 
is  abolished  before  the  motor  functions,  perception  of  pain  and  touch 
being  abolished  at  a  stage  in  which  the  consciousness  is  still  filled  with 
dreams  which  cause  active  movements.  The  observations  of  Hitzig 
have  clearly  demonstrated  this  difference  in  the  susceptibility  of  the 
sensory  and  motor  functions  of  the  cortex. 

During  his  experiments  in  stimulation  of  the  cerebral  cortex,  this  author 
found  that  the  irritability  of  the  motor  portion  of  the  cortex  was  abolished 
only  during  very  deep  ether  narcosis.  "  Even  when  every  trace  of  reflexes 


58     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

had  disappeared,  when  even  the  most  intense  sensory  stimuli,  such  as  those  caused 
by  pulling  on  the  dura  or  by  strong  induction  currents  in  the  nasal  mucous 
membrane,  no  longer  produced  any  reflex  effects  whatever,  some  of  the  motor 
centres  still  reacted  to  local  stimulation."  For  the  pharmacologist  it  is  an 
interesting  fact  that  while  ether  is  finally  able  to  prevent  any  effects  from 
stimulation  of  the  cerebral  cortex,  Hitzig  found  that  morphine  never  weakened 
the  effects  of  such  stimulation,  even  when  very  large  doses  were  administered 
intravenously.  This  clearly  demonstrates  the  fundamental  difference  between 
the  action  of  chloroform  and  ether  and  that  of  morphine  on  the  motor  tracts. 

Bernstein  has  shown  that  the  spinal  cord  of  the  frog  behaves  in  the  same 
fashion  as  the  cerebral  cortex.  This  author,  by  stoppage  of  the  blood  flow  through 
the  lower  portion  of  the  spinal  cord,  protected  this  portion  of  the  cord  from  the 
action  of  chloroform  present  in  the  blood,  and  found  that  the  motor  organs  in 
the  poisoned  portion  of  the  cord  were,  under  these  conditions,  able  to  react  to 
stimuli  reaching  them  from  the  lower  unpoisoned  portion  although  the  sensory 
receptive  organs  in  the  upper  poisoned  portion  were  already  completely  inex- 
citable. 

It  therefore  appears  that  everywhere  in  the  central  nervous  system 
the  motor  organs  become  narcotized  much  later  than  the  sensory  ones. 
It  is  significant,  in  this  connection,  that  the  respiratory  centres,  which 
maintain  the  respiratory  movements  long  after  any  reactions  to  sen- 
sory stimuli  have  ceased  to  occur,  are  automatic  motor  centres. 

Many  facts  indicate  further  that  the  motor  centres  experience 
an  augmentation  of  their  excitability  before  they  are  depressed  by 
these  anaesthetics.  Kr'dpelin,  in  psychophysical  experiments,  was  able 
to  demonstrate  a  facilitation  of  the  inauguration  of  motor  acts  during 
the  earlier  phases  of  the  alteration  of  the  consciousness  produced  by 
ether  and  chloroform,  while,  on  the  other  hand,  perception  was  retarded 
from  the  start.  It  therefore  appears  that  these  two  phases  of  mental 
activity,  the  perception  of  external  impressions  and  the  motor  inner- 
vation,  are  influenced  in  opposite  fashions,  just  as  is  the  case  during 
the  earlier  stages  of  the  action  of  alcohol. 

This  close  relationship  in  the  psychical  effects  of  alcohol  and  of 
small  doses  of  ether  is  also  expressed  by  the  fact  that  ether  too  pro- 
duces a  distinct  euphoria,  which  fact  accounts  for  the  occasional  occur- 
rence of  the  chronic  abuse  of  ether  (Ewald).  It  is  stated  that  in 
Ireland  ether  drinking  is  a  comparatively  wide-spread  vice. 

The  excitability  of  the  peripheral  nerve-trunks  is  certainly  at  first 
markedly  augmented  by  the  local  action  of  chloroform  or  ether,  this 
effect  being  followed  by  a  depression  and  finally  by  the  abolition  of 
their  excitability  if  they  are  further  exposed  to  the  action  of  these 
vapors  (Bernstein,  Waller  and  Bethe). 

The  primarily  stimulating  effect  of  ether  and  chloroform,  like  that  of 
alcohol,  occurs  also  in  vegetable  cells,  Elfving  having  found  the  respiration  of 
plants  to  be  increased  by  these  drugs,  while,  according  to  Kegel,  they  also  increase 
the  assimilation  of  C03. 

"While  the  narcotic  actions  of  ether  and  chloroform  on  the  cerebrum 
differ  from  each  other  only  quantitatively,  when,  disregarding  their 
anaesthetic  actions,  we  investigate  the  disturbances  and  alterations  of 


ANAESTHESIA  59 

function  which  occur  during  anaesthesia,  we  find  very  essential  differ- 
ences in  the  actions  of  these  two  most  widely  used  anaesthetics. 

CERTAIN  DISTURBANCES  OCCURRING  DURING  ANAESTHESIA  are  merely 
mechanical  results  of  the  muscular  relaxation, — for  example,  the 
interference  with  respiration  and  asphyxia,  occasioned  by  the  tongue 
falling  back  on  the  larynx,  and  the  interference  with  the  power  of 
swallowing,  which  may  cause  aspiration  pneumonia.  Another  frequent 
disturbance,  particularly  at  the  start,  is  vomiting,  which  is  probably 
of  central  causation,  and  not  due  to  the  local  irritating  effects  of  the 
anaesthetic  which  may  be  swallowed  with  the  saliva.  [The  local  irritat- 
ing effect  in  the  pharynx  doubtless  at  times  plays  a  role  in  producing 
such  vomiting,  and  it  also  seems  to  the  translator  that  the  local 
irritating  effects,  especially  of  ether,  in  the  stomach,  which  frequently 
appear  to  cause  a  free  secretion  of  hydrochloric  acid,  cannot  be  disre- 
garded as  a  probable  contributory  cause  of  the  nausea  and  vomiting 
which  follow  the  recovery  from  the  anaesthetic. — TR.] 

Annoying  Reflexes. — When  the  vapor  of  ether  or  chloroform  is 
inhaled,  there  occur  a  number  of  reflexes,  just  as  is  the  case  after 
the  inhalation  of  other  irritating  gases,  which  reactions  may  be  con- 
sidered to  be,  as  it  were,  defensive  in  their  nature,  by  the  aid  of  which 
the  organism  endeavors  to  guard  the  respiratory  tract  from  the 
entrance  of  irritating  vapors.  Especially  in  experiments  on  ani- 
mals there  occurs  with  great  regularity  a  stoppage  of  the  respiration 
in  the  phase  of  expiration,  or  violent  expiratory  efforts  and  convulsive 
closure  of  the  pharynx,  which  are  due  to  reflexes  originating  in  the 
nasal  mucous  membrane  as  a  result  of  the  irritation  of  the  terminations 
of  the  trigeminus  (Kratschner) .  The  more  concentrated  the  vapors 
inhaled,  the  more  well  developed  is  this  reflex.  After  a  short  period, 
this  stoppage  of  the  respiration  passes  off,  and  the  breathing  then 
continues  regularly  and  deeply  (see  Fig.  4).  Simultaneously  with 
this  inhibition  of  the  respiration,  there  often  occurs  a  very  pronounced 
slowing  of  the  pulse,  which  also  is  reflexly  induced,  and  at  times  the 
heart  may  cease  to  beat  temporarily.  [This  reflex  inhibition  of  the 
heart  would  appear  to  be  a  contributory  cause  of  death  in  some  cases 
of  sudden  death  at  the  very  commencement  of  chloroform  anaesthesia. — 
TR.] 

In  man  these  reflexes  produce  slighter  effects  than  in  the  rabbit 
or  in  the  cat,  and  consequently,  if  one  commences  the  anaesthetization 
very  gradually,  administering  such  slight  concentrations  of  the  anaes- 
thetic that  they  produce  only  slight  irritation,  and  if  this  concentra- 
tion be  only  gradually  increased,  as  a  rule  these  disturbing  reflexes 
may  be  completely  avoided,  for  the  reflex  centres  will  be  sufficiently 
narcotized  to  prevent  their  reaction  to  the  irritation  caused  when  the 
concentration  of  the  inhaled  anaesthetic  is  great  enough  to  produce  its 
local  irritating  effect  in  the  upper  air-passages. 

The  first  EFFECTS  ON  THE  RESPIRATION  produced  by  the  anaesthetic 


60     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

after  its  absorption  are  an  acceleration  and  deepening  of  the  respira- 
tory movements,  which  may  be  best  observed  in  vagotomized  subjects, 
for  with  intact  vagi  the  reflex  effects  originating  in  the  pulmonary 
nerves  complicate  the  picture.  Knoll *  and  Cushny  go  so  far  as  to 
assume  a  primary  excitation  of  the  respiratory  centre.  In  the  stage 
of  surgical  anaesthesia  the  breathing,  which  during  the  stage  of  excite- 
ment was  irregular,  becomes  regular  and  slightly  slowed,  and,  as  the 
sensibility  is  abolished,  the  respiratory  centre  is  no  longer  affected  by 
any  reflexes,  even  long  before  it  is  itself  depressed  (Cushny).  If  the 
narcosis  is  pushed  beyond  the  necessary  stage,  a  final  stage  follows  in 
which  the  breathing  either  gradually  becomes  shallower  and  shallower 
and  finally  stops  entirely,  or,  but  much  less  frequently,  stops  more  or 
less  suddenly.  In  general,  observations  on  animals  indicate  that  the 
respiratory  centre  resists  the  action  of  full  anaesthetizing  doses  of  ether 
longer  than  it  does  tho-se  of  chloroform,  and  the  practical  experience 
of  surgeons  demonstrates  that  asphyxia  occurs  much  less  frequently 
with  ether  than  with  chloroform. 

ACTION  ON  THE  CIRCULATION 

VASOMOTOR  CENTRES. — There  is  a  much  greater  difference  between 
the  two  anaesthetics  in  respect  to  the  intensity  of  their  effects  on  the 
vasomotor  centres  and  the  heart.  The  vasomotor  centres  controlling 
the  cutaneous  vessels,  and  particularly  those  of  the  face,  are,  from 
the  start,  particularly  depressed  by  ether  and  chloroform,  and  conse- 
quently at  the  start  of  the  narcosis  the  face  becomes  flushed.  When 
chloroform  is  inhaled,  however,  as  a  rule,  the  blood  supply  to  the  skin 
diminishes  as  the  anaesthesia  becomes  deeper,  because  other  vascular 
systems  lose  their  tone  and,  as  a  consequence,  the  blood  leaves  the  skin 
to  go  to  these  other  regions.  With  ether,  on  the  contrary,  the  face 
usually  remains  flushed,  for  the  vasomotor  centres  controlling  other 
vascular  systems  are  much  less  affected  by  it  than  by  chloroform. 

Chloroform  depresses  the  vasomotor  centres  far  more  than  does 
ether,  so  that,  even  when  chloroform  anaesthesia  is  cautiously  induced, 
the  blood-pressure  falls  decidedly,  while  when  ether  is  used  it  may 
for  a  long  time  remain  at  the  normal  level.  In  animal  experiments 
this  difference  may  be  strikingly  demonstrated  if  the  animals  are 
anaesthetized  with  doses  of  these  two  anaesthetics  which  are  just  suffi- 
cient to  induce  anaesthesia.  While  it  is  true  that  if  the  chloroform 
concentration  of  the  blood  is  very  gradually  increased  so  that  complete 
anaesthesia  is  induced  only  after  30-35  minutes  of  absolutely  regular 
administration  of  the  anaesthetic  complete  insensibility  and  complete 
abolition  of  the  reflexes  may  be  obtained  without  inducing  any  fall  in 
the  blood-pressure,  with  the  continued  maintenance  of  the  same  degree 
of  anaesthesia  the  blood-pressure  falls  slowly  and  progressively,  so 
that  after  about  an  hour  it  may  be  reduced  to  one-half  of  the  normal 
height  and  after  2%  hours  to  one-third,  while  the  respiration  may 


THE  CIRCULATION  DURING  ANAESTHESIA 


61 


62     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

continue  regularly  and  normally  (Rosenfeld).  Such  experiments 
indicate  that  the  circulation  is  markedly  impaired  even  by  very 
cautiously  conducted  chloroform  anaesthesia  and  relatively  much  more 
markedly  than  is  the  respiration.  On  the  other  hand,  if  ether  be 
administered  cautiously,  complete  anaesthesia  is  readily  induced  with- 
out causing  any  change  in  the  blood-pressure,  and  even  when  the 
anaesthesia  is  continued  for  hours  the  carotid  pressure  need  fall  but 
slightly.  In  fact,  if  during  a  chloroform  anaesthesia  the  blood-pressure 
has  been  caused  to  fall  slowly  and  progressively  and  ether  be  substi- 
tuted and  the  anassthetization  continued  with  it,  the  blood-pressure 
will  gradually  rise  once  more. 

In  man  the  same  holds  true.  Blauel,  using  Gartner's  tonometer, 
found  that  in  100  ether  anaesthesias  of  average  duration  the  blood- 
pressure  remained  above  the  normal  throughout,  while  in  37  chloro- 
form anaesthesias  it  was  regularly  below  the  normal  level. 

Thus  far  the  fall  in  blood-pressure  during  chloroform  narcosis 
has  been  represented  as  the  result  of  a  depression  of  vasomotor  centres, 
but  without  any  presentation  of  proof  that  this  is  so.  It  is,  however, 
clear  that  a  gradual  diminution  in  the  power  of  the  heart  must  also 
cause  a  fall  in  the  blood-pressure,  and  earlier  investigators  have  attrib- 
uted this  without  question  to  a  weakening  of  the  cardiac  action. 
Scheinesson2  was  the  first  to  observe  vasodilatation  in  the  rabbit's 
ear  during  anaesthesia,  which  he  attributed  to  depression  of  the  vaso- 
motor centres.  In  the  rabbit,  after  section  of  the  vasomotor  nerves  of 
one  ear,  the  inhalation  of  chloroform  causes  a  dilatation  only  of  the 
vessels  of  the  other  ear  whose  nerves  are  still  intact  (Knoll2),  and 
consequently  it  is  evident  that  this  vasodilatation  is  caused  centrally. 
The  acceleration  of  the  blood  flow  from  a  mesenteric  vein  observed 
by  Pick  indicates  that,  when  the  vessels  are  relaxed  during  chloroform 
narcosis,  the  blood  collects  chiefly  in  the  vessels  of  the  lower  abdomen. 
A  similar  depression  of  the  vasomotor  centres  is  caused  by  ether  in  a 
much  slighter  degree  and  only  by  much  larger  doses. 

ACTION  ON  THE  HEART. — It  is  very  possible  that  in  the  usual  chloro- 
form narcosis,  in  addition  to  the  vasomotor  depression,  a  weakening 
of  the  heart  action  is  also  responsible  for  the  gradual  fall  in  blood- 
pressure,  for,  as  will  soon  be  discussed  more  fully,  chloroform  is  a 
powerful  cardiac  poison  in  concentrations  which  are  but  slightly  higher 
than  that  necessary  for  the  induction  of  anaesthesia,  and  consequently 
even  slighter  concentrations  may  well  produce  such  effects  when  acting 
on  the  heart  for  a  considerable  period.  However,  at  the  start  the  fall 
in  blood-pressure  is  chiefly  due  to  the  depression  of  the  vasomotor 
centres.  This  may  be  concluded  from  the  fact  that  it  is  possible  by 
very  slowly  increasing  the  amount  of  chloroform  in  the  blood  to  cause 
complete  paralysis  of  the  vasomotor  centres  while  the  heart  still 
continues  to  beat  relatively  well.  Under  such  conditions  the  vasomotor 
centres  are  found  to  be  completely  insusceptible  to  stimulation  by  even 


CHLOROFORM  A  CARDIAC  POISON  63 

the  most  powerful  stimuli,  such  as  asphyxia  or  a  sudden  anaemia 
produced  by  ligating  all  the  arteries  passing  to  the  brain,  although  at 
this  time  the  moderately  slowed  but  powerful  heart-beats  are  still 
able  to  maintain  the  blood-pressure  at  a  level  corresponding  to  that 
observed  after  the  complete  relaxation  of  the  vessels  which  follows 
section  of  the  cervical  cord. 

The  greater  the  concentration  of  the  chloroform  in  the  blood,  the 
more  evident  does  its  action  on  the  heart  become.  As  a  consequence, 
irregularities  in  the  heart-beat  may  often  be  noted  early  in  a  chloro- 
form anaesthesia,  for  the  percentage  of  chloroform  in  the  blood  neces- 
sary for  the  maintenance  of  a  satisfactory  anaesthesia — according  to 
Pohl  on  an  average  0.035  per  cent. — is  sufficient  to  weaken  the  heart's 
action,  as  shown  by  Sherrington  and  Sowton  in  their  experiments 
on  surviving  mammalian  hearts  perfused  with  blood  containing 
chloroform. 

Moreover,  without  any  direct  participation  of  the  heart,  the  results 
of  the  general  vascular  relaxation  are  dangerous  enough,  for,  as  the 
blood  collects  in  the  splanchnic  vessels,  the  other  portions  of  the  body 
receive  but  little  blood,  the  face  of  the  anaesthetized  subject  becomes 
pale  and  his  skin  cold,  while  the  pulse  becomes  weak,  and  collapse 
may  occur  during  the  anaesthesia. 

Of  greater  practical  importance  than  this  gradual  fall  in  the 
blood-pressure,  occurring  when  chloroform  is  pushed  too  far,  is  the 
sudden  cessation  of  the  cardiac  activity,  which  may  occur  if  too  large 
quantities  reach  the  blood  at  one  time.  With  ether  this  danger  is 
far  less  imminent,  for  the  difference  in  the  concentration  of  the  drug 
which  is  sufficient  for  anaesthesia  and  that  which  causes  cessation  of 
the  heart's  activity  is  much  smaller  with  chloroform  than  with  ether. 
This  is,  from  the  practical  point  of  view,  the  decisive  difference 
between  these  two  anaesthetics. 

CHLOROFORM  A  CARDIAC  POISON. — The  earlier  investigators  also 
noticed  that  chloroform  impaired  the  activity  of  the  heart,  Snow, 
as  early  as  1852,  having  observed  that  the  vapor  of  chloroform  when 
directly  applied  to  the  exposed  heart  stopped  its  beating.  Later, 
Scheinesson  1  demonstrated  that  the  cardiac  activity  was  impaired  by 
the  inhalation  of  chloroform,  and  numerous  later  experiments  in  which 
various  methods  were  employed  have  brought  further  proof  that  this 
is  so.* 

Newer  experimental  methods  have  rendered  it  possible  to  demon- 
strate in  the  most  complete  fashion  the  harmful  effect  of  chloroform 
on  the  isolated  mammalian  heart.  While  these  methods  will  be  more 

*  Among  others,  mention  should  be  made  of  the  interesting  experiments  of 
Gaskell  and  Shore  in  which,  with  the  aid  of  a  cross-circulation  between  two  ani- 
mals, the  blood  containing  chloroform  acted  in  one  only  on  the  central  nervous 
system,  while  in  the  other  it  acted  only  on  the  heart.  In  these  experiments  the 
blood-pressure  always  fell  when  the  blood  containing  the  chloroform  reached  the 
heart. 


64     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

fully  discussed  in  the  chapter  on  the  Pharmacology  of  the  Circulation, 
their  results  are  briefly  given  here.  Bock,  making  use  of  an  experi- 
mental method  in  which  the  blood-pressure  depends  exclusively  on  the 
work  done  by  the  heart,  has  shown  that  the  inhalation  of  chloroform 
mixed  with  air  is  immediately  followed  by  a  fall  in  the  blood-pressure 
and  that  the  heart-beats  are  slowed  independently  of  any  action  on  the 
central  nervous  system,  while  the  inhalation  of  strong  ether  vapor, 
even  when  continued  for  a  considerable  period,  alters  the  blood-pressure 
and  frequency  of  the  heart-beats  but  slightly. 

By  experiments  on  artificially  perfused  hearts  it  has  been  possible 
to  determine  quantitatively  the  great  difference  in  the  action  exerted 
on  the  heart  by  these  two  anaesthetics.  Those  conducted  by  Dieballa 
on  frogs'  hearts,  and  numerous  more  recent  experiments  conducted 
on  surviving  mammalian  hearts,  have  demonstrated  that  the  molecular 
concentrations  of  chloroform  and  ether  which  produce  death  of  the 
heart  are  in  the  proportion  of  1  to  30-35.  PoM  found  0.058  per 
cent,  of  chloroform  in  the  blood  contained  in  the  left  ventricle  of  a 
dog  which  had  been  narcotized  until  the  heart  stopped.*  As,  accord- 
ing to  this  author,  the  concentration  of  chloroform  in  the  blood  when 
the  narcosis  is  deep,  but  while  the  heart  is  still  beating  well,  is  on  the 
average  0.035  per  cent.,  and  according  to  Niclaux  0.05  per  cent., 
these  figures  show  conclusively  how  slight  the  difference  is  between 
the  concentration  necessary  for  the  maintenance  of  anaesthesia  and 
that  which  causes  paralysis  of  the  heart.  Here  we  find  the  explanation 
of  the  cases  of  sudden  heart  death  which  occur  during  chloroform 
anaesthesia.  With  ether  such  cases  do  not  occur. 

CARDIAC  DEATH  IN  CHLOROFORM  NARCOSIS. — In  order  clearly  to 
understand  the  danger  to  which  the  heart  is  exposed  by  the  adminis- 
tration of  concentrated  chloroform  vapor,  one  must  remember  that 
with  incautious  dosage  the  heart  is  the  first  organ  to  be  imperilled. 
In  a  sense  we  are  dealing  with  a  local  action  of  the  chloroform-laden 
blood  on  this  organ,  for  the  blood  which  contains  the  largest  amount 
of  the  anaesthetic  flows  directly  into  the  heart,  and  only  later  is  the 
anaesthetic  distributed  around  in  all  portions  of  the  circulation.  The 
heart  can  therefore  be  very  seriously  poisoned  by  the  sudden  entrance 
into  it  of  blood  containing  too  much  chloroform,  even  before  any 
general  narcosis  has  developed.  If  by  such  abrupt  administration 
of  chloroform  the  action  of  the  left  ventricle  is  markedly  weakened 
for  even  a  short  time,  a  vicious  circle  is  produced,  which  with  each 
instant  augments  the  damage  suffered  by  the  heart,  for,  as  the  heart 
empties  itself  but  incompletely,  it  is  directly  exposed  to  a  persisting 

*  In  one  case  in  which  PoM  had  forced  air  saturated  with  chloroform  into 
the  lungs  and  in  which  immediate  heart  death  occurred,  as  much  as  0.22  per 
cent,  was  found  in  the  blood  contained  in  the  heart.  However,  in  this  case  it 
is  highly  probable  that  a  great  excess  of  chloroform  entered  the  blood  during  the 
last  respiration. 


CARDIAC  DEATH  FROM  CHLOROFORM 


poisonous  action  of  the  blood  stagna- 
ting in  it  and  containing  poisonous 
amounts  of  chloroform,  and  conse- 
quently the  continuation  of  this  con- 
dition results  in  death  of  the  heart. 
This  is  the  reason  why,  when  the  heart 
is  suddenly  paralyzed  by  too  large 
doses  of  chloroform,  it  is  no  longer  pos- 
sible to  revive  it  by  ceasing  the  ad- 
ministration of  the  drug  and  inaugu- 
rating artificial  respiration.    Under 
such  conditions  it  may  be  revived  only    , 
if  this  blood,  which  is  saturated  with    i 
chloroform,    be   removed   from   the 
heart,  which  may  be  accomplished  by    ! 
compression  of  the  thorax,  and  in  case 
of  need  by  the  intravenous  (or  intra- 
cardiac )  administration  of  epinephrin    ! 
1  to  100,000  (see  chapter  on  Circula-    | 
tion)*    [or   by    transdiaphragmatic 
massage  of  the  heart,  which  has  al-    j 
ready  under  such  conditions  been  the    ! 
means  of  saving  a  considerable  num- 
ber of  lives. — TB.] 

As  is  to  be  expected  from  the 
manner  in  which  it  occurs,  chloro- 
form heart  death  presents  a  materi-    J 
ally  different  appearance  from  that 
of  death  due  to  vasomotor  paralysis. 
This  may  be  readily  demonstrated  in    I 
the  laboratory  by  compelling  an  ani- 
mal to  inhale  all  at  once  large  quanti-    < 
ties  of  chloroform,  in  which  case  the    \ 
blood-pressure  falls  more  or  less  sud-     j 
denly  and  the  cardiac  pulsations  dis-    1 
appear  completely.  After  cessation  of 
the  circulation,  however,  several  res- 
piratory movements  occur,  and  in  fact 
convulsions  due  to  asphyxia  may  oc- 
cur just  as  in  any  other  sudden  stop- 
page of  the  circulation.   In  this  case 
the  stoppage  of  the  heart  puts  an  end 
to  life  before  deep  narcosis  has  been 
attained.     (See  Fig.  6.) 

*  Lewis  ("Heart,"  vol.  3.  p.  99ff.)  has 
found  that  even  small  amounts  of  epine- 
phrin will  often  bring  about  fibrillation  in 
hearts  exposed  to  only  moderate  concentrations  of  chloroform.     It  is  therefore  clear 
that  the  use  of  this  drug  under  these  conditions  may  be  dangerous. — TR. 
5 


66      PHARMACOLOGY  OP  CENTRAL  NERVOUS  SYSTEM 

Many  cases  cited  in  the  literature,  in  which  death  has  occurred 
after  a  few  inhalations  of  chloroform,  were  certainly  due  to  such  sud- 
den overloading  of  the  blood  with  chloroform  as  a  result  of  careless 
pouring  on  the  mask  of  too  large  amounts  of  the  anassthetic.  The 
comment  often  made  in  such  cases,  that  death  could  not  have  been 
due  to  administration  of  too  much  chloroform  because  not  enough 
had  been  given  to  produce  narcosis,  is  only  explainable  by  the  fact 
that  the  observer  had  thoroughly  misunderstood  the  true  cause  of 
death. 

Analysis  of  the  Causes  of  Experimental  Chloroform  Death. — In 
considering  the  evidence  which  has  been  furnished  by  animal  experi- 
mentation, in  regard  to  the  causes  of  death  by  chloroform,  it  is  seen 
that  two  forms  may  be  distinguished.  With  the  gradual  absorption  of 
too  large  quantities  of  chloroform,  all  the  organs  succumb  to  the 
poison  in  fairly  equal  degree,  and  the  abolition  of  the  functions  of 
the  different  portions  of  the  central  nervous  system  occurs  in  the 
order  of  their  relative  susceptibility.  As  the  vasomotor  centre  suffers 
very  early,  a  stair-like  fall  in  the  blood-pressure  results  from  the 
general  vascular  paresis,  and  finally  the  respiration  fails,  death  result- 
ing from  the  cessation  of  the  breathing,  although  the  heart  continues 
to  beat  regularly  and  with  a  fair  degree  of  force.  The  heart  is  conse- 
quently the  last  to  die  in  this  form,  which  resembles  the  usual  death 
occurring  in  ether  narcosis.  In  the  other  form,  large  amounts  of 
chloroform  pass  rapidly  into  the  blood  and  paralysis  of  the  heart 
results,  and,  as  the  poisoned  heart  is  unable  to  expel  this  blood,  which 
is  saturated  with  large  amounts  of  chloroform,  from  its  cavities  and 
vessels,  actual  death  of  the  heart  quickly  follows  the  paralysis.  In  this 
form  of  chloroform  death,  the  respiration  continues  after  the  heart 
has  ceased  to  beat. 

.  As  in  practice  intermediate  forms  between,  and  combination  forms  of,  these 
two  occur,  the  consequent  varying  course  and  appearance  of  fatal  chloroform 
accidents  have  led  to  an  active  discussion  as  to  whether  death  in  chloroform 
narcosis  is  due  to  respiratory  or  cardiac  paralysis.  Particularly  the  Paris 
Commission  of  1855,  the  English  Commission  of  1864,  and  the  two  Indian  Com- 
missions of  1889  and  of  1890,  have,  by  means  of  numerous  experiments  on 
different  species  cf  animals,  firmly  established  the  fact  that  a  proper  adminis- 
tration of  not  too  concentrated  chloroform  vapor,  if  persisted  in,  always 
results  in  the  respiration  stopping  first,  while  the  heart  continues  to  beat  for 
some  time — 2  to  12  minutes — longer.  On  the  other  hand,  other  authors  have 
repeatedly  emphasized  the  fact  that  death  may  also  result  from  a  primary 
stoppage  of  the  heart  (Scheinesson,1,1  Schmey,  Cushny,  Ratimoff,  and  others), 
From  what  has  been  said  above,  these  contradictions  in  the  experimental 
results  are  readily  explained  by  the  variations  in  the  experimental  conditions. 

Chloroform  Death  in  Man. — Actual  experience  with  chloroform 
death  in  man  agrees  with  the  experimental  data,  except  that  in  man 
one  often  is  dealing  with  individuals  whose  hearts  have  already  been 
weakened  by  degenerative  changes.  Among  the  autopsy  findings  after 
sudden  death  from  chloroform,  very  frequently  fatty  degeneration 


DEATH  FROM  CHLOROFORM  67 

of  the  heart  is  noted.  Consequently  it  is  easy  to  understand  why  in 
man  death  due  to  the  heart  should  occur  with  relatively  greater 
frequency  than  is  the  case  in  experiments  on  animals. 

If  the  chloroform  accumulates  in  gradually  increasing  amounts  in 
the  blood,  extreme  pallor  of  the  face  and  cyanosis  develop,  as  expres- 
sions of  the  fact  that  the  vasomotor  and  respiratory  centres  have 
become  incapable  of  performing  their  functions,  and  asphyxia  occurs 
while  the  heart  continues  to  beat.  If  in  such  cases  artificial  respiration 
be  instituted  promptly  enough,  the  natural  respiratory  movements, 
as  a  rule,  start  up  again  as  soon  as  the  excess  of  chloroform  has  been 
eliminated.  However,  cases  do  occur  in  which  the  respiration  does  not 
return  although  the  heart  clearly  continues  to  beat  for  some  time 
longer. 

Nothnagel  and  Rossbach  mention  such  a  case  in  which  artificial  respiration 
was  carried  on  in  a  most  efficient  fashion  for  half  an  hour,  as  long  as  the  heart 
continued  to  beat,  without  any  reappearance  of  the  voluntary  respirations.  Quite 
characteristic  of  such  irreparable  respiratory  paralysis  in  the  presence  of  a 
heart  which  continued  to  beat  well,  is  the  description  of  Jenop's  case  of  a  man, 
aged  48,  to  whom  chloroform  was  to  be  administered  on  account  of  the  amputation 
of  a  finger.  "  The  patient  was  more  restless  than  usual  and  was  completely 
anaesthetized  after  the  administration  of  not  more  than  two  drachms  of  chloro- 
form. The  operation  was  about  to  start,  when  he  snorted  two  or  three  times, 
suddenly  became  blue  in  the  face  and  ceased  breathing,  while  the  radial  pulse  be- 
came very  weak.  The  heart  sounds  were  audible  for  20  minutes  longer,  during 
which  time  no  visible  respiratory  movements  occurred."  All  attempts  at  revival 
were  unsuccessful.  Post-mortem  examination  disclosed  nothing  of  any  particular 
moment. 

If  the  face  of  the  chloroform  patient  suddenly  becomes  pale,  the 
pupils  dilate  and  become  fixed,  the  pulse  disappears,  and  the  heart 
ceases  to  beat,  while  the  respiration  continues  for  some  time,  the  pros- 
pects for  revival  are  much  less  favorable.  This  is  the  picture  seen 
in  heart  death  due  to  sudden  overloading  of  the  pulmonary  blood 
with  chloroform.  Such  accidents  occur  usually  at  the  commencement 
of  the  anesthesia,  when  the  patient  is  violently  excited  and  the  anaes- 
thetist attempts  to  attain  surgical  ansesthesia  too  rapidly,  or,  with  an 
excited  patient,  endeavors  to  control  him  by  incautiously  pouring  too 
much  chloroform  on  the  mask.  From  many  typical  reports  of  such 
cases,  the  following  may  be  cited  from  Schmey : 

For  the  purpose  of  removing  a  gland  from  the  submaxillary  region  in  a 
man  of  45  years,  anaesthesia  was  started.  "  At  the  very  start,  however,  when  only 
a  few  cubic  centimetres  of  chloroform  had  been  poured  on  the  mask,  the  patient 
suddenly  became  pulseless,  but  continued  to  breathe  quietly  and  deeply  several 
times  more.  Artificial  respiration  was  instituted,  and  a  pulsation  in  the  radial 
artery  could  be  clearly  felt  each  time  pressure  was  made  on  the  thorax.  If 
then  the  artificial  respiration  was  stopped,  natural  breathing  was  continued  for 
a  short  time,  but  no  spontaneous  pulse  in  the  radial  artery  could  be  felt.  Arti- 
ficial respiration  was  instituted  again  with  the  same  effect,  and  this  was  con- 
tinued for  longer  than  an  hour  with  similar  results."  The  autopsy  disclosed 
marked  fatty  degeneration  of  the  heart. 

In  many  cases  of  death  occurring  at  the  start  of  the  anassthesia, 
death  has  been  attributed  to  the  effects  of  shock,  and  cases  certainly 


68     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

vouched  for  (Nussbaum)  do  in  fact  demonstrate  that,  under  similar 
circumstances  of  marked  excitement  in  especially  feeble  persons,  car- 
diac death  may  result  from  varying  sensory  stimuli  without  any 
anaesthetic  whatever  having  been  administered.  It  is  not  inconceiv- 
able, consequently,  that  the  first  inhalations  of  the  irritating  vapors  of 
chloroform  or  ether  may  cause  death  through  their  reflex  effects  on  the 
respiration  and  the  heart  without  there  being  any  question  of  an  over- 
dose having  been  administered.  However,  these  reflex  effects  which 
have  been  mentioned  before,  the  stoppage  of  the  respiration  in  expira- 
tion and  the  inhibitory  stoppage  of  the  heart,  are  much  less  pronounced 
in  man  than  in  animals  and  pass  off  rapidly.  It  is  very  improbable  that 
they  play  any  important  role  in  the  accidents  of  anaesthesia,  especially 
as  these  reflex  effects  are  by  no  means  slighter  when  ether  is  inhaled 
than  when  chloroform  is  administered,  and  yet  such  accidents  occur 
more  frequently  with  the  latter  anaesthetic.  In  any  case,  especially 
if  the  narcosis  be  gradually  induced,  the  reflex  inhibition  of  the  heart 
may  be  certainly  prevented  by  previously  administering  atropine 
(1/2  ing.)  and  the  marked  reflex  effects  on  the  respiration  by  that  of 
morphine  (0.01-0.2  !  gm.). 

Avoidability  of  Ancesthetic  Accidents. — The  foregoing  discussion 
of  the  dangers  to  the  respiration  and  circulation  which  attend  anaes- 
thesia shows  clearly  that  the  boundary  between  sleep  and  death  in  deep 
narcosis  is  small  enough.  However,  at  the  same  time  our  knowledge 
of  the  causes  of  these  dangers  makes  it  equally  clear  that,  in  the  great 
majority  of  cases,  these  accidents  may  be  avoided,  for  they  are  practi- 
cally always  the  results  of  a  faulty  management  and  incautious  do-sage 
of  the  ancesthetic. 

The  anaesthetic  methods  of  the  day  are  very  susceptible  of  an 
improvement  which  would  permit  of  an  exact  and  reliable  means  of 
varying  and  controlling  the  degree  of  narcosis  produced.  However, 
even  with  the  methods  usually  employed  at  the  present  time,  it  is  pos- 
sible to  avoid  these  dangers  if  the  anaesthetist  understands  the  condi- 
tions controlling  the  absorption  and  elimination  of  the  anaesthetic 
and  is  thus  in  a  position  to  appreciate  correctly  the  causes  of  these 
possible  dangers. 

LAWS  GOVERNING  THE  ABSORPTION  AND  DISTRIBUTION  OF  ANAES- 
THETIC GASES. — The  absorption  of  chloroform  or  ether  vapors  by  the 
blood  depends  on  the  plasma's  coefficient  of  absorption  for  these  gases 
and  on  the  temperature  and  the-  partial  pressure  of  the  anaesthetic  in 
the  alveolar  air.  As  the  absorption  coefficient  at  body  temperature 
may  be  considered  as  constant,  the  absorption  of  chloroform  or  ether 
at  any  instant  is  directly  proportional  to  the  partial  pressure  of  the 
anaesthetic  in  the  inspired  air, — i.e.,  to  its  volume  per  cent. 

It  goes  without  saying  that  the  more  the  functional  nervous  ele- 
ments are  permeated  by  the  anaesthetic  the  more  pronounced  will  be 
its  action  on  the  nervous  system.  The  distribution  of  chloroform  or 
ether  throughout  the  organism  follows  certain  well-defined  laws,  the 


ABSORPTION  AND  DISTRIBUTION  OF  ANAESTHETICS   69 

cells  of  all  tissues,  and  especially  those  of  the  nervous  system,  having 
a  greater  affinity  for  them  than  has  the  plasma.  The  cause  of  this 
unequal  partition  of  the  anaesthetic  between  the  nutrient  fluid  and  the 
cellular  elements  has  been  found,  as  will  be  more  fully  discussed  later, 
to  lie  in  the  greater  power  to  dissolve  chloroform  with  which  the  cells 
are  endowed  on  account  of  the  presence  in  them  of  fat-like  or  lipoid 
substances  such  as  cholesterin,  lecithin,  etc.  According  as  the  cells 
in  different  regions  contain  larger  or  smaller  amounts  of  such  lipoids, 
they  absorb  larger  or  smaller  quantities  of  chloroform.  In  consequence, 
therefore,  of  their  greater  power  of  dissolving  the  anaesthetic,  the 
tissues  absorb  it  in  greater  concentration  from  the  blood,  and  conse- 
quently, at  the  commencement  of  every  narcosis,  the  blood  returns  to 
the  right  heart  from  the  systemic  circulation  containing  less  chloro- 
form than  is  carried  to  the  tissues  from  the  left  heart.  According  to 
Nicloux's  analyses,  venous  blood  of  dogs,  even  when  full  anaesthesia 
has  been  maintained  for  a  considerable  period,  contains  on  an  average 
0.05  per  cent,  of  chloroform  while  the  arterial  blood  contains  0.06-0.07 
per  cent.  At  the  commencement  of  anaesthetization  this  difference  is 
naturally  much  greater,  and  consequently  when  the  anaesthetic  is 
administered  incautiously  the  left  heart  is  much  more  exposed  to 
danger  than  is  the  right.  For  example,  PoM  found  0.22  per  cent, 
of  chloroform  in  the  blood  of  the  left  ventricle  but  only  0.02  per  cent, 
on  the  right  side  in  a  dog  in  which  he  had  brought  about  a  sudden 
cardiac  death  by  the  rapid  administration  of  air  saturated  with 
chloroform.  Such  are  the  conditions  in  those  cases  in  which  the 
overloading  of  the  blood  in  the  lungs  with  chloroform  may  poison  the 
left  heart  before  the  chloroform  is  sufficiently  distributed  and  absorbed 
by  the  other  tissues  and  consequently  before  any  narcosis  develops.  On 
the  other  hand,  when  a  properly  induced  anaesthesia  is  at  its  height,  the 
central  nervous  system  contains  relatively  more  chloroform  than  does 
the  blood. 

However,  the  tissues  are  never  able  to  remove  all  the  chloroform 
from  the  blood.  On  the  contrary,  with  continuous  inhalation  a  condi- 
tion of  equilibrium  between  blood  and  tissue  cells  must  gradually 
be  established,  which  corresponds  to  the  distribution  coefficient  of  the 
solubility  of  the  chloroform  in  the  blood  fluid  and  in  the  body  tissues. 
When,  on  the  other  hand,  further  administration  ceases  and  the 
elimination  through  the  lungs  commences,  so  that  the  concentration  in 
the  blood  diminishes,  it  necessarily  follows  that  the  chloroform  moves 
in  the  reverse  direction,  from  the  tissues  back  into  the  blood.  Naturally, 
with  persisting  elimination  the  normal  functions  are  again  established. 

These  phenomena  may  be  compared  with  extraction  by  agitation 
when  a  substance  less  soluble  in  water  than  in  another  fluid,  used  as  an 
extractor,  distributes  itself  between  the  two  fluids  and,  in  accordance 
with  its  greater  solubility  in  the  second  fluid,  accumulates  in  larger 
quantities  therein,  and  yet  may  be  removed  from  this  fluid  again  if 
repeatedly  extracted  with  pure  water.  In  the  body,  chloroform  at 


70      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

each  moment  distributes  itself  between  the  blood  and  tissues  in 
accordance  with  its  relative  solubility  therein,  just  as  occurs  in  the 
method  of  extraction  by  shaking. 

The  amount  of  chloroform  present  in  the  central  nervous  system 
is  consequently  always  proportional  to  the  a/mount  present  in  the  blood 
supplying  this  organ.  Step  by  step  it  follows  the  chloroform  partial 
pressure  as  it  rises  or  falls  in  the  blood.  The  amount  of  chloroform 
present  in  the  blood  is,  however,  for  its  part  also  dependent  in  an 
entirely  similar  fashion  on  the  chloroform  partial  pressure  in  the 
inspired  air, — i.e.,  on  the  volume  per  cent,  of  its  vapor  in  the  alveoli. 
The  depth  of  narcosis  consequently  is  increased  or  diminished  in 
direct  proportion  to  the  concentration  of  the  anaesthetic  in  the  air 
inspired. 

The  various  events  and  happenings  in  anesthesia  thus  occur  in  the 
following  fashion. 

In  the  lungs  there  occurs  an  exchange  between  the  blood  and  the 
inspired  air  in  which,  with  a  given  concentration  of  chloroform  in  the 
air,  the  blood  absorbs  from  it  a  certain  portion,  and  consequently  at 
the  start  less  of  the  anaesthetic  is  contained  in  the  expired  than  in  the 
inspired  air.  For  example,  Harcourt  found  0.55  per  cent.  CHC13  in 
the  inspired  air  but  only  0.34  per  cent,  in  that  expired  at  this  time, 
this  showing  that  the  blood  had  given  up  a  considerable  portion  of  its 
chloroform  to  the  tissues.  This  continues  until  a  condition  of  equilib- 
rium has  been  established  between  the  chloroform  content  of  the  blood 
and  that  of  the  tissues.  In  the  meantime,  so  long  as  the  blood  returns 
to  the  lungs  from  the  tissues  poorer  in  chloroform  than  when  it  left 
them,  it  must  compensate  for  this  loss  by  absorbing  chloroform  from 
the  alveolar  air  until  the  chloroform  tension  of  the  blood  and  the 
alveolar  air  is  equalized.  With  the  inhalation  of  a  mixture  with 
constant  chloroform  content,  there  is  a  constant  flow  of  chloroform 
from  the  inspired  air  to  the  blood  and  from  this  to  the  tissue  cells 
until  the  chloroform  tension  of  the  tissues  and  of  the  blood  has  become 
equal  to  that  of  the  air  inspired.  When  this  state  has  been  attained, 
the  percentage  of  chloroform  in  the  blood  and  in  the  tissues*  remains 
unchanged  as  long  as  the  amount  of  the  chloroform  in  the  air  respired 
remains  constant.  If  the  chloroform  content  of  the  air  breathed  be 
increased,  the  same  play  as  formerly  repeats  itself,  more  chloroform 
being  taken  up  by  the  blood  and  consequently  more  being  absorbed 
by  the  tissues  from  the  blood  until  the  partial  pressure  of  chloroform 
in  the  tissues,  in  the  blood,  and  in  the  alveolar  air  has  again  become 
equal.* 

If  the  administration  of  chloroform  ceases  entirely,  the  blood  at 
the  start  gets  rid  of  the  chloroform  very  rapidly,  and,  corresponding 

*  Recent  analyses  by  Nicloux  give  0.05  per  cent,  of  chloroform  and  0.13-0.14 
per  cent,  of  ether  as  average  figures  for  the  amounts  of  these  substances  present 
in  the  blood  during  deep  anaesthesia. 


RECOVERY  FROM  ANAESTHESIA 


to  its  lessened  tension  in  the  blood,  chloroform  rapidly  passes  from  the 
tissues  into  the  blood  and  thus  starts  a  current  in  the  opposite  direc- 
tion,— i.e.,  from  the  tissues  through  the  blood  to  the  expired  air.  If 
the  air  inspired  contains  no  chloroform,  the  chloroform  contained 
in  the  nervous  system  after  a  short  time  becomes  so  diminished  that 
it  is  no  longer  sufficient  to  maintain  narcosis,  and  the  patient  wakes 
up.  The  last  portions  of  the  chloroform,  however,  are  relatively  slowly 
eliminated,  for  the  tissues  possess  a  much  stronger  affinity  for  the 
drug  than  that  of  water.  This  gradual  diminution  of  the  chloroform 
present  in  the  blood  of  anaesthetized  dogs  is  illustrated  in  the  following 
table  of  Nicloux,  in  which  it  may  be  seen  that  chloroform  may  be 
recognized  in  the  blood  even  seven  hours  after  discontinuation  of  its 
administration. 

Chloroform  Content  of  Blood  after  Termination  of  Anaesthesia. 


Time  elapsed  since  termination 
of  anaesthesia 

Per  cent,  of  chloroform  in  blood 

Exp.  1 

Exp.  2 

0  minutes     

0.054 
0.0255 
0.0205 
0.018 
0.0135 

0.0595 

5  minutes       

15  minutes                

30  minutes  

0.023 
0.018 
0.0075 
0.0015 

1  hour         

3  hours           

7  hours  

The  elimination  of  ether  from  the  blood  takes  place  somewhat  more 
rapidly,  which  explains  the  more  rapid  recovery  from  ether  narcosis. 

Ether  Content  of  Blood  after  Termination  of  Anaesthesia. 


Per  cent,  of  ether  in  blood 


of  anaesthesia 

Exp.  l 

Exp.  2 

0  minutes  

0.115 

0.159 

3  minutes  

0.071 

0.108 

5  minutes  

0.063 

0.080 

1  5  minutes  

0.052 

0.058 

1  hour  

0.025 

0.021 

2  hours 

0  004 

LAWS  GOVERNING  DOSAGE. — The  symptoms  in  narcosis  make  it  clear 
that  a  certain  degree  of  saturation  of  the  tissues  with  the  anaesthetic 
corresponds  to  every  variation  of  the  partial  pressure  of  the  gas  in  the 
alveolar  air.  The  depth  of  the  anaesthesia  is  consequently  at  every 
moment  dependent  on  the  partial  pressure  of  the  anaesthetic  in  the  gas 
mixture  respired. 


72     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

From  this  law,  first  propounded  by  the  French  physiologist  P.  Bert, 
follows  the — for  the  management  of  anaesthesia — extremely  important 
conclusion,  that  the  depth  of  the  narcosis  and  the  danger  thereof  is  not 
at  all  dependent  on  the  absolute  amount  of  the  anaesthetic  which  has 
been  used,  but  upon  the  concentration  of  the  anaesthetic  in  the  air 
respired.  The  control  and  modification  of  the  degree  of  action,  which 
with  non-volatile  drugs  is  attained  by  modification  of  the  absolute 
size  of  the  dose,  is,  during  the  administration  of  gases,  attained  by 
modification  of  the  concentration  administered.  Consequently  in  every 
moment  of  the  anaesthesia  a  sufficient  dilution  of  the  ancesthetic  with 
air  is  an  essential  condition. 

With  anaesthetics,  just  as  with  non-volatile  drugs,  the  therapeutic 
and  toxic  doses  must  be  determined.  With  them  it  is  necessary  to 
establish  the  concentrations  which  produce  a  safe  anaesthesia  of  suffi- 
cient depth,  and  one  which  may  be  maintained  for  some  time  without 
injury,  and  to  find  out  at  which  concentrations  the  dangerous  accidents 
may  occur.  The  therapeutically  efficient  and  toxic  concentrations 
represent  the  limits  for  safe  depth  of  anaesthesia.  Paul  Bert  called  this 
interval  the  ' '  zone  maniable. ' ' 

Since  the  time  of  Bert  many  experiments,  and  in  recent  times 
with  methods  free  from  objections,  have  been  undertaken  in  order  to 
determine  the  therapeutically  effective  and  the  toxic  concentrations  of 
chloroform  and  ether,  and  the  figures  obtained  agree  closely  enough 
for  practical  purposes.  Bert  V  found  1.5  volume  per  cent,  of  chloro- 
form vapor  in  the  inspired  air  sufficient  to  produce  narcosis,  but  this 
figure  is  too  high,  for  Kiorika 2  found  that  the  concentration  suitable 
to  induce  and  maintain  narcosis  lies  between  0.6  and  1.2  volumes  per 
cent. 

The  following  table  gives  the  results  of  Rosenf 'eld's *  experiments  in 
which  he  investigated  the  intensity  of  the  action  produced  in  rabbits 
by  different  mixtures  of  air  and  chloroform; 


Relationship  between  the  Percentage  of  Chloroform  and  Ether  in  the  Respired  Air  and 
the  Depth  of  the  Ancesthesia  (Rosenf eld,  Spenzer). 


Chloroform,  percent- 
age by  volume 

Time  necessary  to  in- 
duce ansesthesia 

Depth  of  anaesthesia 
or  narcosis 

Remarks 

0.54-0.69  

2hrs  

No  narcosis  

Only  somnolence. 

0.96-1.01  

30-40  min  

Complete  

Blood-pressure  at  first 

1.16-1.22  

30  min  .  .  . 

Complete 

normal  then  gradual 
fall  for  4  hrs.     Res- 
piration normal. 
Cessation  of  respiration 

1.41-1.47  

37  min  

Deep  

at  end  of  2  hrs. 
As  above  after  1  hr. 

1.63-1.65  

12  min.    . 

Deep            

As  above  after  30  min. 

DOSAGE  OF  ANAESTHESIA 


73 


Relationship  between  the  Percentage  of  Chloroform  and  Ether  in  the  Respired  Air  and 
the  Depth  of  the  Anaesthesia  (Rosenfeld,  Spenzer) — Continued. 


Ether,  percentage 
by  volume 

Time  necessary  to  in- 
duce anaesthesia 

Depth  of  anesthesia 
or  narcosis 

Remarks 

1.5  

2  hrs  

Hardly  any  

Only  slight  somnolence. 

2.5  

Very  incomplete  .  . 

Reflexes  maintained. 

3.2-3.6  

25  min  

Complete  

Respiration    and  car- 

4.45   

15  min  

Complete  

diac  function  re- 
mained good  for 
hours. 
Respiration    slow    and 

60... 

regular;  pulse  accel- 
erated. 
Respiration    ceased    in 

8-10  minutes. 

As  may  be  seen  from  this  table,  for  rabbits  the  efficient  dose  of 
ether  lies  between  3.5  and  6.0  per  cent,  by  volume.  In  man  similar 
concentrations  are  sufficient,  as  shown  by  Dreser,1  who,  at  the  height 
of  deep  ether  narcosis,  collected  air  from  under  the  mask  and  found 
in  it  on  the  average  3.7  per  cent,  by  volume. 

It  is  thus  seen  that  a  concentration  of  about  1  per  cent,  by  volume 
of  chloroform  vapor  is  sufficient  to  maintain  a  complete  anaesthesia 
in  the  rabbit,  even  for  as  long  as  four  hours,  with  the  respiration 
remaining  normal  and  the  blood-pressure  falling  only  very  slowly. 
However,  anaesthesia  is  induced  only  very  slowly  with  this  low  and 
consequently  safe  concentration.  A  concentration  only  slightly  higher 
— for  example,  1.6  per  cent. — induces  anaesthesia  much  more  rapidly, 
but  with  this  concentration  the  respiration  may  stop  when  its  inhala- 
tion has  been  continued  for  half  an  hour.  It  is  consequently  clear  that 
the  limit  of  safety  is  much  smaller  for  chloroform  than  with  ether,  and 
this  difference  in  the  size  of  the  difference  between  the  therapeutic  and 
the  toxic  concentration  of  the  two  ancesthetics  is  merely  the  exact 
expression  and  explanation  of  the  now  generally  accepted  clinical  con- 
clusion that  chloroform  narcosis  is  attended  with  a  greater  direct 
danger  to  life  than  is  ether  narcosis.  The  comparison  of  the  figures 
for  the  concentrations  necessary  for  the  induction  of  anaesthesia  shows 
further  that  with  ether  the  percentage  by  volume  present  in  the 
respired  air  must  be  at  least  three  times  larger  than  is  the  case  with 
chloroform. 

AFTER  DANGERS  OF  ETHER  NARCOSIS. — In  ether  narcosis  an  over- 
dosage  lasting  for  a  short  time  is  by  no  means  so  likely  to  produce 
direct  disturbances  of  the  circulation  and  respiration  as  is  the  case  with 
chloroform.  On  the  other  hand,  if  the  permissible  concentration  be 
exceeded,  local  irritant  effects  in  the  respiratory  mucous  membrane 
result.  A  mixture  of  air  with  7  per  cent,  of  ether  vapor  is  quite 
irritant  to  the  mucous  membrane  of  the  larynx  and  causes  a  reflex 


74     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

cough,  and  at  times  a  temporary  closure  of  the  glottis,  causing  a  feeling 
of  suffocation  (Dreser2).  However,  these  reflexes,  which  act,  as  it 
were,  as  sentinels  to  prevent  the  entrance  of  irrespirable  vapors  into 
the  lower  air-passages,  soon  cease  if  the  ether  inhalation  is  continued, 
and  the  sensibility  is  thus  further  depressed.  These  irritant  actions 
affect  at  the  start  the  mucous  membranes  of  the  mouth,  the  naso- 
pharynx, and  the  upper  air-passages.  The  salivary  glands  especially 
are  stimulated  to  active  secretion,  and,  as  the  anaesthetized  individual 
can  neither  expectorate  nor  swallow,  mucus  and  saliva  collect  in  large 
amounts  in  the  mouth  and  throat.  Rattling  respiration  results,  and 
bronchitis  or  pneumonia  may  develop  some  time  later.  It  is  ques- 
tionable whether  these  inflammations  are  due  to  the  direct  irritation 
produced  by  the  ether  vapor  in  the  tracheal  and  bronchial  mucous 
membranes,  or  whether  they  result  from  the  aspiration  into  the  lungs 
of  the  saliva  and  mucus  secreted  so  profusely  ( Grossmann,  Holscher, 
Klipsteiri).  A  hypodermic  of  atropine  or  scopolamine  preceding  the 
ether  narcosis  will  entirely  prevent  or  markedly  lessen  this  hyper- 
secretion. 

CHLOROFORM  ANESTHESIA  ALSO  is  FOLLOWED  BY  DANGEROUS  AFTER 
EFFECTS  if  too  high  concentrations  are  administered,  or  even  if  the 
proper  concentrations  are  administered  for  too  long  a  tune,  fatty 
degeneration  of  the  liver,  of  the  heart,  and  of  the  kidneys  developing 
under  these  conditions,  all  lesions  which  may  be  regularly  demon- 
strated in  animals  after  a  single  long-continued  chloroformization  oi 
same  (Ungar,  Strassmann,  Ostertag).  They  are  due  to  a  toxic  action 
on  the  cells  of  these  internal  organs,  which  occurs  along  with  the 
narcosis  of  the  brain,  but  which  is  not  dependent  on  the  cerebral 
actions,  for  they  may  be  caused  by  repeated  subcutaneous  injection  of 
non-narcotic  doses  of  chloroform,  which  produce  similar  lesions  in 
the  same  organs  (Nothnagel).  The  very  intense  fatty  infiltration  of 
the  liver  and  of  the  heart,  sometimes  observed,  is  the  expression  of  a 
very  severe  cell  destruction  ( Rosen f 'eld2  u.  Eubow}. 

These  experimental  findings  make  clear  the  cause  of  those  fatal 
cases  in  which,  after  chloroform  anaesthesia,  death  occurs  with  the 
symptoms  of  serious  liver  disease  or  those  of  increasing  cardiac  weak- 
ness and  coma  (Bandler}  Ambrosius,  Frdnkel,  Kast  u.  Mester).  The 
harmful  after-effects  on  the  kidney  are  evidenced  by  the  frequent 
appearance  of  albumin  and  casts  in  the  urine  (Rindskopf) .  In  addi- 
tion, an  increased  destruction  of  proteid  and  the  appearance  in  the 
urine  of  pathological  decomposition  products  of  proteids  have  been 
proved  to  occur  (Kast  u.  Mester). 

After  ether  all  these  metabolic  disturbances  are  by  no  means  so 
pronounced  as  after  chloroform.  In  particular,  Selbach's  experiments 
have  shown  that  even  long-continued  and  frequently  repeated  ether 
narcoses  do  not  so  readily  cause  the  death  of  animals  as  do  repeated 
chloroform  narcoses. 

From  what  has  been  said  it  is  evident  that  almost  all  of  the  dangers 


ANAESTHETIC  METHODS  75 

of  anesthesia  are  due  to  the  administration  of  too  high  concentrations 
of  the  anaesthetics.  With  chloroform  even  a  slight  overdosage  directly 
imperils  life,  while  the  after-effects  of  ether  on  the  respiratory  organs 
are  usually  due  to  the  inhalation  for  a  considerable  time  of  ether  vapor 
which  is  insufficiently  diluted  with  air. 

DROP  METHOD. — It  follows  that  the  drop  method  is  the  only  one 
permissible  for  the  administration  of  the  more  dangerous  chloroform, 
for  by  this  method  the  dosage  may  be  physiologically  varied, — i.e., 
may,  according  to  the  observation  of  the  symptoms  of  the  anaesthetized 
patient,  be  administered  drop  by  drop,  at  times  more  rapidly  and 
at  times  more  slowly,  when  once  the  necessary  depth  of  anaesthesia 
has  been  attained. 

In  order  to  avoid  the  reflexes  produced  by  too  concentrated  vapor,  the 
administration  should  be  started  very  gradually,  at  the  rate  of  about  20  drops 
in  the  minute,  this  rate  being  gradually  increased  to,  at  the  most,  60  drops 
in  the  minute,  and,  when  surgical  anaesthesia  has  been  attained,  the  number  of 
drops  should  again  be  diminished.  On  account  of  the  lower  boiling  point  of  ether, 
it  is  much  more  difficult,  when  using  the  drop  method  and  a  loosely  applied 
mask,  to  produce  the  concentration  of  the  vapor  which  is  needed  for  the  induction 
of  anaesthesia,  and  even  with  the  use  of  closely  applied  masks  it  is  not  always 
possible  to  produce  surgical  anaesthesia  by  administering  ether  according  to  the 
drop  method.  Consequently,  formerly  ether  was  usually  poured  into  the  so-called 
half-closed  masks,  which  were  covered  with  impermeable  material. 

Surgical  experience  has  shown  that  these  methods  permit  of  anaes- 
thetization  with  a  satisfactory  degree  of  safety,  but  they  possess  the 
drawback  that  the  rapidity  with  which  the  drops  should  follow  each 
other  from  moment  to  moment  is  entirely  dependent  upon  a  subjective 
estimate  by  the  anaesthetist,  and  that  it  is  impossible  under  such 
conditions  to  estimate  accurately  how  much  of  the  anaesthetic  actually 
gets  into  the  air  inspired  under  the  momentary  conditions.  Many 
attempts  have  therefore  been  made  to  construct  apparatus  which  with 
greater  certainty  may  be  adjusted  for  certain  concentrations. 

ANESTHETIZING  APPARATUS. — The  first  attempts  to  conduct  anaesthesia  in 
man  with  such  measured  mixtures  were  made  by  Paul  Bert.3  Dreser3  and  Gep- 
pert,  Kionka,1,*  Kermish,  and  many  others  have  constructed  various  apparatus 
by  the  use  of  which  the  uncertainties  and  accidents  of  anaesthesia  should  be 
eliminated.  These  exact  apparatus  are,  however,  too  complicated  for  general 
use,  and  have  therefore  not  been  widely  adopted.  The  Roth-Drager  apparatus 
is  one  of  the  most  widely  used,  and  in  it  the  anaesthetic  is  administered  diluted 
with  oxygen.  An  absolute  guarantee  of  the  concentration  of  the  anaesthetic  in 
the  respired  air  can  be  furnished  only  by  such  apparatus  as  lead  an  already 
measured  mixture  directly  into  the  air-passages  but  not  through  a  more  or  less 
closely  applied  mask.  Such  apparatus  are  used  in  animal  experiments  (Kro- 
necker,  Ratimoff,  Cushny)  but  the  same  principle  may  be  utilized  for  man. 

DEPENDENCE  OF  ABSORPTION  OF  THE  TYPE  OF  RESPIRATION. — If  the 
anaesthetic  be  dropped  on  the  mask  or  administered  by  means  of 
apparatus  through  a  mask  which  is  not  closely  applied,  the  amount 
which  is  actually  respired  is  markedly  influenced  by  the  rate  and  qual- 
ity of  the  respirations.  With  each  inspiration  air  from  the  outside 
rushes  under  and  through  the  mask,  and  consequently  rapid  and  deep 


76      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

breathing  on  the  part  of  the  patient  causes  a  dilution  of  the  vapor 
under  the  mask,  while  the  expirations  force  out  a  large  portion  of  the 
anaesthetic  which  may  be  present  in  the  mask,  and  thus,  with  active 
respiration,  only  a  small  portion  of  the  anaesthetic  used  actually  reaches 
the  lungs.  On  the  other  hand,  depression  of  the  respiration  necessarily 
to  a  high  degree  favors  the  accumulation  of  the  anaesthetic  inside  the 
mask,  and  consequently,  when  for  a  considerable  period  the  respira- 
tion is  feeble,  the  air  in  the  mask  contains  higher  percentages  of  the 
anaesthetic. 

INDIVIDUAL  SUSCEPTIBILITY  OR  IDIOSYNCRASY. — Consequently  a 
painstaking  observation  of  the  respiration  is  essential,  no  matter  what 
method  is  used  in  the  ansesthetization,  and,  at  the  same  time,  all 
the  other  symptoms  must  be  closely  watched,  for  even  in  animals  the 
susceptibility  of  different  individuals  of  the  same  species  to  anaes- 
thetics varies,  and  in  man  the  susceptibility  is  subject  to  wide  varia- 
tions, just  as  is  the  case  with  alcohol.  Consequently,  as  expressed 
by  v.  MikuUcz,1  every  anesthetization  is  a  new  experiment  that  must 
})e  continually  controlled  according  to  the  reaction  of  the  organism. 

Estimated  by  the  average  consumption  of  chloroform  in  the  unit 
of  time,  women  are  generally  more  readily  narcotized  than  men,  and 
the  resistance  is  greatest  in  middle  life.  It  is  well  known  with  what 
difficulty  chronic  alcoholics  are  anaesthetized. 

COMPARATIVE  MORTALITY. — If  the  effects  of  chloroform  be  compared 
with  those  of  ether,  the  facts  already  mentioned  are  alone  sufficient 
to  show  that,  when  the  permissible  concentration  is  exceeded,  the 
direct  danger  to  life  is  very  much  greater  in  chloroform  narcosis  than 
in  ether  narcosis.  The  statistics  of  the  Deutsche  Gesellschaft  fiir 
Chirurgie,  1903,  place  the  mortality  at  one*  death  in  3000  for  chloro- 
form, and  only  one  in  14,600  for  ether.* 

Moreover,  chloroform  narcoses  of  rather  long  duration,  even  when 
carefully  conducted,  are  accompanied  by  other  dangers  to  the  organ- 
ism (p.  74) ,  which  cannot  be  avoided  and  which  occur  very  rarely  when 
ether  is  used.  The  hypersecretion  which  may  cause  serious  after- 
effects when  ether  is  used  may,  on  the  other  hand,  be  avoided  by  the 
previous  administration  of  atropine  or  scopolamine.  Finally,  the 
toxic  action  of  chloroform  on  the  heart  forbids  its  use  in  patients  with 
circulatory  disease. 

That,  in  spite  of  all  this,  chloroform  is  used  so  much  is  explained 
by  the  fact  that  complete  anaesthesia  is  much  more  easily  obtained  with 
chloroform  than  with  ether.  For  operations  lasting  but  a  short  time 
the  analgesia  alone  is  sufficient,  which  is  already  present  in  the  stage 
of  excitement  produced  by  ether,  the  so-called  half -narcosis  (Sudeck, 
Mikulicz  2). 

*  [Recent  American  statistics  give  the  mortality  as  one  in  2048  for  chloro- 
form and  one  in  5623  for  ether.  (Gwathmey,  J.  of  A.M. A.,  1912,  vol.  lix, 
p.  1845).— TB.] 


CHLOROFORM  AND  ETHER  77 

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Nothnagel  u.  Rossbach:  Handb.  d.  Arzneimittellehre,  6th  Edition,  p.  412,  Ber- 
lin, 1887. 

*  Nothnagel:  Berl.  klin.  Woch.,  1866. 

Nussbaum:  Ueber  Chloroformwirkung,  Breslau,  1884. 

Ostertag:  Virchow's  Arch.,  vol.  118. 

Pick,  Fr.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42,  p.  399. 

Pohl:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28. 

Ratimoff:  Du  Bois'  Arch.  f.  Physiol.,  1884,  p.  576. 

Richter,  0.:  Med.  Klin.,  1907,  No.  10. 

Rindskopf:  Deut.  med.  Woch.,  1893,  No.  40. 

Rosemann:  Pfliiger's  Arch.,  1901,  vol.  86,  p.  307,  here  literature. 

*Rosenfeld:  Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  37. 

'Rosenfeld:  Studien   liber    Organverfettungen,   Arch.   f.    exp.    Path.    u.    Pharm., 

1906,  vol.  55. 

Rubow:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  52. 
1Scheinesson:  Diss.,  Dorpat,  1868. 

*  Scheinesson :  Archiv.  d.  Heilkunde,  1869,  p.  172. 


Schmey,  F.:  Inaug.-Diss.,  Berlin,  1885,  p.  11. 

Selbach:   Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  34. 

Sherrington  and  Sowton:  Br.  Med.  Journal,  1904. 

Snow:   London  Journal  of  Medicine,  18o2. 

Spenzer,  I.  G.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  33. 

Strassmann:  Virchow's  Arch.,  vol.  115. 

Sudeck:  Deut.  med.  Woch.,  1901. 

Ungar:  Vierteljahrschrift  f.  gerichtl.  Med.,  vol.  47. 

Waller:  Brain,  1896. 

Zeller:  Zeitschr.  f.  physiol.  Chemie,  1883,  vol.  8,  p.  70. 


COMBINED  ANAESTHESIA 

In  order  to  avoid  the  chief  disadvantages  of  ether,  which  are  pre- 
sented by  the  slow  or  difficult  induction  of  insensibility  and  the  usually 
very  pronounced  stage  of  excitement,  the  anaesthesia  is  often  started 
with  chloroform  and  then  continued  with  ether.  The  use  of  ethyl 
bromide  (Kocher)  for  this  purpose  has  been  properly  abandoned.* 
It  has  also  been  possible  to  augment  the  anaesthetic  effects  of  ether  by 
combining  it  with  other  narcotics. 

Soon  after  the  introduction  of  general  anaesthesia,  on  purely  empiri- 
cal grounds  it  was  found  advantageous  to  make  use  of  mixtures  of 
ether  and  chloroform,  often  with  the  addition  of  alcohol,  in  prefer- 
ence to  using  either  of  these  anaesthetics  alone.  Apparently  anaes- 
thesia with  such  mixtures  is  less  attended  by  the  danger  of  depression 
of  the  heart  and  respiration  than  is  pure  chloroform  anaesthesia. 

In  such  mixtures  the  alcohol  plays  hardly  any  other  role  than  that 
of  diluent  (Filehne  and  Biberfeld),  for  it  is  only  the  diminution  of 
the  vapor  tension  of  the  anaesthetics,  caused  by  the  addition  of  the 
alcohol,  which  can  be  of  any  significance,  for,  in  its  presence,  the 
evaporation  of  the  actually  efficient  constituents  of  the  mixture  is 
retarded,  and  thus  the  danger  of  overdosage  is  lessened. 

With  the  combination  of  ether  and  chloroform,  on  the  other  hand, 
newer  investigators  of  the  reciprocal  synergistic  effect  of  the  narcotics 
have  raised  the  question  whether  the  narcotic  actions  of  ether  and 
chloroform,  when  thus  used,  are  simply  superimposed  on  each  other, 
or  whether,  as  has  also  been  assumed,  they  synergistically  produce  an 
increased  effect.  In  the  first  case,  half  of  the  vapor  concentration  of 
ether  necessary  to  produce  anaesthesia  and  half  of  the  similarly  effective 
concentration  of  chloroform  should  be  sufficient  to  produce  anaesthesia, 
but  should  do  no  more  than  this.  If,  on  the  other  hand,  by  their  simul- 
taneous action  a  synergistic  increase  in  their  action  results,  perhaps 
on  account  of  a  greater  absorption  of  chloroform  by  the  nervous 
tissues  (Fuhner),  the  total  effect  should  be  greater  than  would  be 
expected  from  the  simple  addition  of  their  separate  effects. 

*  [In  the  United  States  the  less  dangerous  ethyl  chloride  is  widely  used 
as  a  means  of  easily,  safely,  and  pleasantly  starting  the  anaesthesia,  and  where  it 
has  been  used  has  met  with  much  favor. — TB.] 


MORPHINE-SCOPOLAMINE  ANAESTHESIA  79 

Honigmann  believes  that  he  has  been  able,  by  experiments  on  animals,  to 
show  that  this  greater  effect  is  produced,  yet  the  average  values  obtained  in  his 
experiments  do  not  indicate  this,  but  only  those  obtained  under  special  conditions. 
On  the  other  hand,  Madelung,  by  continuously  administering  exactly  measured 
mixtures  of  ether  and  chloroform,  was  able  to  produce  only  that  degree  of 
anaesthesia  which  was  to  be  expected  as  a  result  of  a  simple  addition  of  the 
separate  effects.  In  his  experiments  mixtures  containing  less  than  half  the 
amount  of  chloroform  necessary  to  produce  anaesthesia  failed  to  produce  anaes- 
thesia when  combined  with  a  concentration  of  ether  equal  to  one-half  of  the 
anaesthetizing  concentration.  His  results  agree  with  those  obtained  by  Biirgi, 
who  was  also  unable  to  obtain  any  synergistic  strengthening  of  the  action  of 
the  hypnotics  of  the  alcohol  group,  chloral  hydrate  and  urethan,  whose  action 
is  in  principle  the  same  as  that  of  chloroform  and  ether.  The  advantage  (  ?TB.) 
of  anaesthesia  induced  by  such  mixtures  may  consequently  be  attributed  only  to 
the  fact  that  the  dangerous  actions  of  chloroform  are  exerted  in  the  production 
of  only  one-half  of  the  total  narcotic  effect. 

BIBLIOGRAPHY 

Biirgi:  Deut.  med.  Woch.,  1910,  No.  1. 

Filehne  u.  Biberfeld:  Zeitschr.  f.  exp.  Path.  u.  Therap.,  1906,  vol.  3,  p.  171. 

Fuhner:   Berichte  d.  deut.  Chem.  Ges.,  1909,  vol.  42,  p.  887. 

Fuhner:   Deut.  med.  Woch.,  1910,  No.  2. 

Honigmann:   Arch.  f.  klin.  Chir.,  1899,  vol.  58. 

Kocher:  Chirurg.  Operationslehre,  Jena,  Fischer,  1902. 

Madelung:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  409. 

MORPHINE-SCOPOLAMINE  ANAESTHESIA 

On  the  other  hand,  by  combination  with  substances  like  morphine 
and  scopolamine,  which  depress  the  central  nervous  system  in  a  dif- 
ferent manner,  it  is  possible  to  produce  a  distinct  augmentation  of  the 
narcotic  effects  of  the  gaseous  anaesthetics.  A  preliminary  injection 
of  0.01  gm.  of  morphine  with  0.5  mg.  of  scopolamine  not  only  prevents 
that  stage  of  excitement  which  ordinarily  is  so  disturbing  at  the 
commencement  of  anaesthesia,  but  in  addition  it  renders  it  possible  to 
induce  and  maintain  a  satisfactory  anaesthesia  with  distinctly  lower 
concentrations  of  the  anaesthetic  in  the  air  inspired. 

In  experiments  on  animals  it  has  been  possible  to  confirm  this  clinical  ex- 
perience in  an  exact  fashion,  Madelung,  after  previous  injection  of  doses  of 
morphine  and  scopolamine,  which  by  themselves  produce  no  narcotic  effects,  hav- 
ing been  able  to  induce  a  deep  narcosis  with  air  containing  only  2.5-3  volume 
per  cent,  of  ether,  although  the  controls  which  had  not  received  such  injections 
required  4.5  per  cent,  of  the  anaesthetic  for  the  induction  of  equally  deep  anaes- 
thesia. Consequently,  after  the  previous  administration  of  these  two  drugs, 
human  beings  may  be  satisfactorily  anaesthetized  with  minimal  amounts  of  chloro- 
form, or,  in  case  ether  be  used,  they  may  be  readily  anaesthetized  by  the  safe 
drop  method.  In  addition,  scopolamine  possesses  the  advantage,  as  has  already 
been  mentioned  (p.  76 ),  of  inhibiting  the  secretion  of  saliva. 

As  stated  by  Schneiderlin,  Korff,  and  many  others,  it  is  possible  to  produce 
with  morphine  and  scopolamine  alone  a  condition  of  analgesia  and  clouded 
consciousness  (twilight  sleep)  in  which  even  relatively  major  operations  may  be 
painlessly  performed.  It  was  such  observations  which  first  directed  attention 
to  the  striking  intensification  of  the  effects  of  morphine  which  is  caused  by 
scopolamine  and  which  may  be  readily  demonstrated  in  experiments  on  animals 
( Kochmann ) . 

Some  time  ago  morphine-scopolamine  narcosis  was  actually  recom- 
mended as  a  substitute  for  the  general  anaesthesia  induced  by  inhala- 


80     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

tion;  but  further  clinical  experience,  supported  by  the  results  of 
experiments  on  animals,  has  demonstrated  that  those  doses,  which  with- 
out the  aid  of  one  of  the  gaseous  anaesthetics  cause  a  narcosis  of 
sufficient  depth,  carry  with  them  greater  dangers  than  any  of  the  other 
various  methods  of  producing  ancesthesia  (Kochmann). 

In  principle,  any  narcosis  produced  by  injecting  a  drug  must  repre- 
sent a  step  backward  when  contrasted  with  anaesthesia  produced  by 
inhalation,  for,  when  non-volatile  narcotics  are  administered,  one  loses 
the  greatest  of  advantages, — namely,  the  ability  to  interrupt  the 
anaesthesia  at  the  appearance  of  dangerous  symptoms,  and  to  secure 
the  elimination  of  the  drug  in  the  most  rapid  manner  possible  by 
elimination  through  the  lungs.  Doses  of  morphine  and  scopolamine 
which,  when  given  together,  prepare  the  patient  satisfactorily  for 
an  anaesthesia  by  inhalation  are  without  danger.  At  the  present  time 
they  are  also  often  employed  to  produce  a  certain  degree  of  cloudiness 
of  the  consciousness  and  loss  of  memory  during  parturition  (Gauss, 
Kronigt  Mans f eld,  Bjorkenheim).  When  used  for  this  latter  indi- 
cation, the  morphine  should  be  cautiously  administered,  in  order  to 
avoid  the  danger  to  the  respiration  of  the  new-born  child,  which  has 
already  been  mentioned  on  page  35.  While  0.3-0.6  to  1.0  mg.  of  scopo- 
lamine, administered  in  several  injections,  may  be  safely  given,  it  is 
not  well  to  increase  the  dose  of  morphine  beyond  0.01  gm.  in  labor  cases. 

BIBLIOGRAPHY 

Bjorkenheim:  Ergehnisse  d.  Geburtshilfe  u.  Gynakologie,  1911,  vol.  2,  p.  1. 

Gauss:  Archiv  f.  Gynakologie,  vol.  78. 

Kochmann:  Arch.  int.  de  Pharmacodynamie,  1903,  vol.  12. 

Kochmann:  Mtinchn.  med.  Woch.,  1905. 

Korff:  Munch,  med.  Woch.,  1901,  No.  29. 

Kronig:  Deut.  med.  Woch.,  1908,  No.  23. 

Mansfeld:  Wien.  klin.  Woch.,  No.  1. 

Madelung:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  409. 

Schneiderlin;  Aerztliche  Mitteil.  aus  &  f.  Baden,  May,  1900, 

NITROUS  OXIDE  ANAESTHESIA 

The  great  majority  of  accidents  during  chloroform  and  ether  nar- 
coses  occur  during  minor  operations,  for  which  one  attempts  to  induce 
an  anaesthesia  of  short  duration  too  rapidly  and  without  sufficient 
assistance.  The  introduction  of  nitrous  oxide,  as  a  means  of  rapidly 
producing  a  narcosis  of  short  duration,  was  consequently  an  important 
step  of  progress,  although  to-day  local  anaesthesia  has  almost  entirely 
driven  this  method  out  of  the  field  for  minor  surgical  procedures. 

Nitrous  oxide,  N2O,  whose  powers  of  causing  intoxication  are  responsible 
for  the  discovery  of  inhalation  anaesthesia,  was  actually  introduced  into  practice 
only  at  a  much  later  date,  the  sixth  decade  of  the  last  century. 

This  substance  is  a  colorless  gas  with  a  weak,  sweetish  odor,  heavier  than 
air,  and  rather  soluble  in  water.  It  is  prepared  by  heating  ammonium  nitrate, 
NH4NO3,  which  is  readily  decomposed  into  N2O  +  2H2O.  It  may  be  obtained  com- 
mercially, condensed  under  high  pressure  in  iron  cylinders. 


NITROUS  OXIDE  81 

Like  hydrogen  or  nitrogen,  nitrous  oxide  when  inhaled  produces 
no  irritating  effects.  Although  able,  outside  of  the  body,  to  support 
combustion  even  better  than  air,  in  the  body  it  is  unable  to  maintain 
the  respiratory  changes  of  the  tissues.  Consequently,  nitrous  oxide 
may  be  administered  for  only  a  very  short  time  if  it  be  inhaled  pure 
and  free  from  oxygen. 

The  possibility  of  utilizing  in  practice  the  inhalation  of  pure 
nitrous  oxide  depends  upon  the  fact  that,  during  the  very  rapid 
absorption  of  this  gas  by  the  blood,  narcosis  is  produced  before  suffo- 
cation. That  nitrous  oxide  narcosis  is  not  due  to  this  suffocation  alone 
is  quite  evident  from  the  fact  that  the  typical  convulsions  due  to 
asphyxia  do  not  occur  in  warm-blooded  animals  when  it  is  administered 
alone,  although  with  complete  withholding  of  oxygen  without  the 
action  of  any  narcotic  such  convulsions  would  necessarily  occur  at 
the  end  of  the  first  minute. 

If  a  human  being  be  caused  to  inhale  undiluted  nitrous  oxide  with 
complete  exclusion  of  the  air,  and  the  expired  air  or  gases  be  permitted 
to  escape  through  a  valve,  a  condition  resembling  intoxication  rapidly 
develops,  and  after  about  one  minute  the  consciousness  disappears  and 
anaesthesia  and  relaxation  of  the  muscles  appear  at  the  same  time  with 
rather  pronounced  cyanosis.  If  now  the  patient  be  allowed  to  breathe 
air  again,  the  anaesthesia  lasts  about  half  a  minute  longer,  and  at  the 
end  of  another  half  minute  recovery  occurs  rapidly  (Binz). 

It  is  thus  evident  that,  when  pure  nitrous  oxide  unmixed  with  air 
is  breathed,  unconsciousness  results  at  a  much  less  dangerous  stage  of 
asphyxia  than  is  the  case  with  pure  suffocation  (Zuntz  and  Goldstein], 
If  animals  continue  to  breathe  nitrous  oxide  after  the  dyspnrca,  which 
at  the  start  was  inspiratory  in  character,  has  altered  its  type  to  the 
expiratory  one,  the  convulsions  which  ordinarily  occur  during  suffo- 
cation do  not  occur,  and  the  animals  die  as  a  result  of  asphyxia,  the 
heart  continuing  to  beat  for  a  considerable  period  after  the  respiration 
has  become  paralyzed. 

The  narcotic  action  of  nitrous  oxide  may  be  especially  well  demonstrated 
on  the  frog,  which  is  not  affected  by  the  lack  of  oxygen  in  the  atmosphere  except 
after  many  hours.  Although  these  animals,  when  kept  in  an  atmosphere  of 
hydrogen  for  hours  at  a  time,  remain  reflexly  excitable  and  capable  of  motion, 
when  placed  in  pure  nitrous  oxide  they  quickly  become  motionless  and  no  longer 
react  to  sensory  irritation  such  as  that  produced  by  the  application  of  acetic 
acid  to  the  skin.  If  now  the  frog  be  again  brought  into  the  air,  after  a  few 
minutes  reflex  excitability  and  the  motor  function  return.  The  very  interesting 
experiments  of  Paul  Bert,  to  which  we  will  soon  return  again,  have  clearly  shown 
that  nitrous  oxide  produces  a  narcotic  effect  in  man  even  when  all  elements  of 
suffocation  or  asphyxia  are  excluded,  provided  only  that  the  blood  be  saturated 
with  a  sufficient  quantity  of  this  gas, 

If  nitrous  oxide,  diluted  with  enough  oxygen  to  prevent  suffo- 
cation, be  inhaled,  symptoms  are  observed  which  L.  Hermann  thus 
describes,  from  experiments  made  upon  himself:  "One  perceives  the 

6 


82     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

distinctly  sweetish  taste  of  the  gas,  and  soon  buzzing  and  drumming 
in  the  ears  are  felt,  visual  impressions  become  very  indistinct,  and 
there  is  a  feeling  of  increased  warmth  and  of  extraordinary  lightness 
of  the  limbs,  this  latter  probably  being  due  to  the  loss  of  the  muscle 
sense. ' '  The  muscular  movements  become  very  uncertain ;  there  is  some 
depression  of  the  susceptibility  to  painful  impressions  and  to  a  less 
degree  to  touch.  ' '  The  flow  of  ideas  is  abnormally  rapid,  and  usually 
there  is  loud  laughing.  Consciousness  is  never  completely  abolished, 
and  complete  anaesthesia  also  does  not  occur.  If  the  inhalation  of  the 
gas  is  then  interrupted,  the  normal  condition  is  very  quickly 
re-established. ' ' 

A  complete  narcosis  does  not  result  from  the  breathing  of  nitrous 
oxide  diluted  with  oxygen,  for  the  reason  that  the  partial  pressure  of 
nitrous  oxide  in  a  mixture  containing  21  volumes  per  cent,  of  oxygen 
is  not  sufficient  to  cause  the  blood  to  absorb  a  sufficient  amount  of 
this  relatively  feeble  narcotic.  For  the  production  of  a  complete 
anesthesia  the  partial  pressure  of  the  nitrous  oxide  must  reach 
760  mm.  of  Hg,  one  atmospheric  pressure.  In  order  to  attain  this 
it  is  necessary  either  to  have  the  nitrous  oxide  administered  undiluted, 
— that  is  to  say,  under  a  pressure  equivalent  to  one  atmosphere, — and 
under  such  conditions  asphyxia  will  quickly  follow  on  the  anaesthesia, 
or,  as  was  first  done  by  Paul  Bert,  20  per  cent,  of  oxygen  is  intro- 
duced under  pressure  into  nitrous  oxide  without  increasing  its  volume, 
and  this  mixture  is  administered  under  a  pressure  of  one  and  one- 
fifth  atmospheres.  This  author  was  able  to  show  that  in  this  fashion  it 
is  possible  without  danger  to  produce  and  to  maintain  a  deep  narcosis. 

However,  the  actual  handling  of  such  narcotic  mixtures  under 
pressure  is  too  complicated  for  every-day  use,  and  consequently  nitrous 
oxide  is  employed  only  for  narcoses  lasting  but  a  very  short  time,  in 
which  case  the  pure  gas  is  administered,  or  for  light,  incomplete  anaes- 
thesia, in  which  nitrous  oxide  with  oxygen  is  administered.  Pure 
nitrous  oxide  may  be  allowed  to  flow  from  the  cylinder  into  a  rubber 
bladder  from  which  it  is  inhaled  through  a  mouth-piece,  the  expired 
air  escaping  through  a  valve.  A  simple  readjustment  of  the  apparatus 
permits  the  administration  of  air  at  the  end  of  the  first  minute.  For 
the  incomplete  anaesthesias  one  administers  a  mixture  of  80  per  cent, 
nitrous  oxide  and  20  per  cent,  oxygen,  the  so-called  laughing  gas, 
which,  under  ordinary  atmospheric  pressure,  produces  only  a  condition 
resembling  intoxication,  which  is  entirely  free  from  danger  and  in 
which  there  is  a  simple  clouding  of  the  consciousness  with  analgesia. 

Nitrous  oxide  mixed  with  enough  oxygen  to  support  the  respiration 
(20-15  per  cent.)  does  not  produce  complete  anaesthesia,  because  under 
such  a  partial  tension  of  four-fifths  of  an  atmosphere  the  nitrous 
oxide  does  not  become  sufficiently  concentrated  in  the  blood.  However, 
in  combination  with  doses  of  morphine  and  scopolamine,  which  are 


ETHYL  BROMIDE  83 

in  themselves  entirely  safe  and  which  alone  produce  no  narcotic 
effects,  the  effect  of  such  mixtures  of  nitrous  oxide  and  oxygen  is 
sufficient  to  produce  a  satisfactory  anaesthesia.  In  this  way  laughing 
gas  may  be  utilized  for  anaesthesias  lasting  for  considerable  periods 
and  is  adapted  to  major  operations  (Neu).  The  chief  advantages  of 
such  anaesthesias  are  that  nitrous  oxide  produces  no  irritating  effects 
on  the  respiratory  organs  and  but  slight  side  actions,  and  that  recov- 
ery occurs  with  unusual  rapidity.  After  cessation  of  its  administration 
the  nitrous  oxide  content  of  the  blood  very  rapidly  falls  below  the 
minimal  amount  which  produces  any  effect.  Animals  may  become 
entirely  normal  within  1-2  minutes  after  the  interruption  of  the  deep 
anaesthesia  produced  by  this  method. 

BIBLIOGRAPHY 

Bert,  P.:  Gazette  med.  de  Paris,  1878  and  1879. 

Binz:  Vorles,  p.  37. 

Hermann,  L. :  Lehrb.  d.  exp.  Toxikol.,  Berlin,  1874,  p.  244. 

Neu:  Munch,  med.  Woch.,  1910,  No.  36. 

Zuntz  u.  Goldstein:   Pfluger's  Arch.,  vol.  17. 

ETHYL  BROMIDE,  C2H5Br,  is  a  colorless  volatile  fluid,  boiling  at 
38-39°  C.  It  is  readily  decomposed  under  the  influence  of  light 
and  air,  and  should  consequently  be  kept  in  brown  bottles  as  nearly 
full  as  possible.  It  may  now  be  obtained  in  very  pure  form,  but  prep- 
arations colored  brown  are  not  to  be  used. 

ETHYL  BROMIDE  ANESTHESIA  has  some  advantages  similar  to  those 
of  nitrous  oxide  anaesthesia,  for  it  is  much  more  readily  induced  and 
conducted.  When  a  considerable  amount — say  5.0-10.0  gm. — of  ethyl 
bromide  is  poured  into  the  half -closed  impermeable  mask,  the  anaes- 
thesia develops  extremely  rapidly  after  10-20  inhalations.  If  within 
one  and  one-half  minutes  the  desired  effect  has  not  been  obtained, 
its  administration  is  not  to  be  continued,  for  this  would  be  attended 
with  considerable  danger.  When  the  drop  method  is  employed  for 
the  administration  of  ethyl  bromide,  the  anaesthesia  also  develops 
comparatively  rapidly,  and  the  stage  of  excitement  is  ordinarily  com- 
paratively short  and  the  recovery  from  the  narcosis  is  rapid.  After 
recovery,  a  taste  of  garlic  in  the  mouth  and  a  similar  odor  on  the 
breath,  which  often  lasts  for  24  hours  or  longer,  is  very  disagreeable 
and  disturbing.  Vomiting  occurs  much  less  frequently  than  after 
chloroform. 

However,  ethyl  bromide  should  not  be  employed  for  deep  or  com- 
plete anaesthesia,  because  the  respiratory  function  is  markedly  affected 
by  it,  cessation  of  respiration  occurring  almost  simultaneously  with 
the  abolition  of  the  reflexes.  It  is  also  unsuitable  for  operations  lasting 
for  a  considerable  period,  because  the  anaesthesia  is  likely  to  run  along 
somewhat  irregularly,  and  especially  because,  as  a  result  of  its  long- 


84     PHARMACOLOGY  OP  CENTRAL  NERVOUS  SYSTEM 

continued  action  in  the  body,  secondary  disturbances  and  injury  to 
the  internal  organs  occur  to  an  even  greater  extent  than  after  chloro- 
form and  may  produce  serious  late  effects.  Dreser  has  demonstrated 
these  late  effects  in  animals. 

BIBLIOGRAPHY 
Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36. 

HYPNOTICS  OF  THE  ALCOHOL  GROUP 

Another  group  of  substances,  which  in  their  basic  actions  follow 
the  type  of  the  alcohol  group,  are  used  as  hypnotics.  As  such  we 
may  use  those  members  of  the  alcohol  group  whose  behavior  in  respect 
to  their  absorption  makes  it  possible  to  confine  their  action  to  that 
of  the  very  early  stage,  and  to  maintain  this  first  stage  for  hours. 
However,  a  regular  and  not  too  rapid  absorption  and  a  gradual  elimina- 
tion are  not  in  themselves  sufficient  to  make  all  the  substances  of 
the  alcohol  group  possessing  these  qualities  utilizable  as  hypnotics, 
for  with  many  a  primary  motor  excitation  produces  disturbing  effects, 
and  in  others  harmful  side  actions  on  the  respiration  and  circulation 
or  on  the  metabolism  are  too  readily  caused  when  the  therapeutic 
dose  is  exceeded. 

The  pharmacological  action  of  the  hypnotics  is  in  all  essential 
points  typical  of  that  of  the  alcohol  and  chloroform  group.  With 
such  an  hypnotic  as  chloral  hydrate,  it  is  possible  to  observe  and  to 
distinguish  all  the  stages  of  narcosis  when  it  is  administered  to  higher 
laboratory  animals,  such  as  rabbits.  At  the  start  the  first  thing 
noted  is  that  the  animals  move  less  frequently  than  usual  and  react 
less  to  psychic  impressions.  In  addition  to  this  action  on  the  cerebrum, 
even  in  the  first  stage,  the  centres  in  the  midbrain,  cerebellum,  and 
medulla,  which  control  motor  coordination,  are  also  affected.  In  the 
second  stage  the  depression  of  the  cerebrum  is  more  pronounced  and 
the  centres  of  coordination  are  still  more  affected,  so  that  the  animal 
is  no  longer  able  to  rise  up  but  remains  lying  on  the  side.  In  this 
stage  the  corneal  reflex  is  diminished,  but  the  respiration  is  only 
slightly  slowed,  while  the  weakened  resistance  shown  by  the  animal, 
when  the  attempt  is  made  to  extend  its  legs,  indicates  that  the  spinal 
cord,  too,  is  involved  in  the  narcosis.  In  contrast  to  the  effect  of  mor- 
phine, the  animal  in  this  stage  reacts  more  actively  to  painful  stimuli 
than  does  a  normal  one,  kicking  actively  when  pinched  and  raising  itself 
up  for  a  short  time.  These  pain  reflexes  become  feeble  only  gradually, 
and  disappear  only  when  the  corneal  reflex  is  almost  completely  abol- 
ished and  when  pulling  on  the  extremities  no  longer  excites  resistance 
(Koppen).  Finally,  in  the  last  stage  all  the  reflexes,  including  the 
corneal,  are  completely  abolished,  the  breathing  becomes  slower,  and 
death  finally  results  from  paralysis  of  the  respiration. 


THE  HYDROCARBON  HYPNOTICS  85 

SIDE  ACTIONS. — With  different  hypnotics  the  blood-pressure  behaves 
differently  in  the  different  stages,  and  the  respiration  is  also  affected 
in  different  degrees.  After  choral  hydrate,  for  example,  as  a  result 
of  vasomotor  depression,  the  blood-pressure  falls  markedly  in  the 
second  stage  at  a  time  when  the  corneal  reflex  is  still  present.  The 
heart-beat  is  also  slowed  early  and  the  respiration  is  distinctly  dimin- 
ished in  frequency.  With  other  hypnotics,  on  the  other  hand,  dis- 
turbances of  the  circulatory  and  respiratory  centres  and  depression 
of  the  heart  develop  only  in  the  last  stages,  just  a  short  time  before 
the  abolition  of  the  corneal  and  all  other  reflexes. 

From  the  above  description  it  may  be  seen  that  the  complete 
narcotic  action  affects  the  centres  in  the  different  portions  of  the 
central  nervous  system,  but  that,  following  the  general  type  of  the 
action  of  the  alcohol  and  chloroform  group,  the  depression  first  affects 
the  cerebrum  and  then  the  spinal  cord,  while  the  vital  centres  in  the 
medulla  are  the  last  to  be  markedly  affected. 

It  is  only  in  the  first  stage  of  the  action  of  the  hypnotics  that  a 
condition  develops  which  corresponds  to  normal  sleep.  Under  their 
influence  dogs  fall  asleep,  assuming  their  normal  sleeping  posture, 
but  they  may  be  readily  awakened  at  any  time,  the  muscle  tone  relaxing 
as  in  normal  sleep  while  the  breathing  is  no  more  slowed  than  in  normal 
sleep.  The  only  difference  appears  to  be  that  on  waking  from  such 
artificial  sleep  the  disturbance  of  coordination  is  more  marked  than  on 
waking  from  natural  sleep,  this  effect  persisting  longer  than  the  others 
after  waking.  It  is  only  these  first  grades  of  their  pharmacological 
actions  which  are  utilized  when  these  substances  are  employed  as 
hypnotics,  the  essential  factor  being  the  depression  of  the  excitability 
of  certain  of  the  cerebral  sensory  functions.  The  hypnotics  heighten 
the  threshold  for  the  conscious  perception  of  sensory  impressions,  this 
being  just  what  is  necessary  for 

FALLING  ASLEEP. — Unfortunately,  our  knowledge  of  the  physiologi- 
cal causation  of  falling  asleep  is  not  satisfactory.  Probably  the  accu- 
mulation of  fatigue  substances,  formed  during  the  activity  of  the  ner- 
vous system,  gradually  produces  the  tendency  to  fall  asleep.  When 
this  has  occurred,  it  is  under  normal  conditions  sufficient  to  cause  an 
individual  to  fall  asleep,  if  the  stimuli  from  the  outer  world,  which  are 
constantly  reaching  the  brain  through  the  organs  of  sense,  are  weak- 
ened as  much  as  possible.  When  endeavoring  to  fall  asleep,  we  darken 
the  room  and  shut  out  noises,  secure  an  equable  warmth,  and  free 
ourselves  from  uncomfortable  clothing, — in  short,  we  purposely  cut 
out  all  the  stronger  stimuli  which  act  on  the  organs  of  sense,  and, 
as  a  rule,  this  is  sufficient,  for,  in  the  quiet  state  which  precedes 
the  dropping  asleep,  feebler  stimuli  no  longer  reach  our  consciousness. 

Causes  of  Insomnia. — The  essential  factor  of  the  so-called  essential 
sleeplessness  is  an  over-excitability  of  the  cerebral  cortex,  as  a  conse- 
quence of  which,  normal  stimuli,  which  ordinarily  are  subliminal,  in 


86      PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

spite  of  the  quiet,  still  reach  the  consciousness  when  the  attempt  is 
made  to  go  to  sleep.  Sleeplessness  may,  however,  even  with  a  normal 
excitability  of  the  cerebral  cortex,  be  due  to  too  powerful  stimuli,  such 
as  psychical  activity,  excitement  produced  by  feelings  of  discomfort, 
sorrow,  etc.,  which  may  prevent  sleep,  or  external  pathological  stimuli, 
like  pain,  dyspnoea,  cough,  etc.,  may  produce  the  same  effects.  In 
such  cases,  in  which  severe  bodily  symptoms  interfere  with  the  falling 
asleep,  the  sleeplessness  is  best  relieved  by  removal  of  these  pathological 
irritations,  if  this  can  be  done.  For  example,  digitalis  will  be  the 
best  hypnotic  if  disturbances  of  the  heart  be  the  cause  of  the  sleep- 
lessness. If,  however,  it  is  not  possible  to  remove  the  cause  of  the 
pathological  stimuli,  the  prevention  of  the  perception  of  these  stimuli 
will  permit  sleep. 

In  the  case  of  pain,  cough,  or  dyspnoea,  this  is  best  accomplished 
by  that  specific  pain  reliever,  morphine.  In  essential  sleeplessness,  not 
due  to  abnormal  stimuli  but  primarily  the  result  of  pathological  excita- 
bility of  the  cerebral  cortex,  the  hypnotics  of  the  alcohol  group  are 
far  more  useful  than  the  morphine  group.  On  the  other  hand,  in  the 
presence  of  severe  pain,  they  are  effective  only  in  doses  large  enough 
to  cause  a  general  narcosis  of  numerous  cerebral  centres.  Such  doses 
may  be  employed  in  the  presence  of  extreme  degrees  of  marked 
cerebral  excitement,  for  example  in  maniacal  patients,  and  may  pro- 
duce the  necessary  quieting  effect  even  on  the  cerebral  motor  centres. 
The  proof  that  small  doses  of  hypnotics  produce  no  other  effect  than 
to  prevent  sensory  stimuli  from  reaching  the  consciousness  has  been 
best  supplied  by  Krapelin's  experiments  in  which  he  tested  the  effect 
of  various  waking  stimuli  in  light  sleep  and  in  sleep  produced  by 
hypnotics. 

INFLTJENCE  OF  HYPNOTICS  ON   THE  DEPTH  OF  SLEEP 

When  the  brain  is  over-excitable,  one  cannot  fall  asleep,  because  even  the 
slightest  stimuli  wake  one  up.  If  the  drowsy  condition  of  falling  asleep  has 
once  passed  over  into  a  condition  of  unconscious  sleep,  under  normal  conditions 
the  sleep  rapidly  becomes  deeper  and,  although  individuals  show  marked  differ- 
ences in  this  respect,  the  maximum  soundness  of  sleep  is  usually  attained  inside 
of  the  first  hour.  Systematic  experiments,  in  which  it  was  determined  what 
intensity  of  noise  was  sufficient  to  wake  the  subject  up  after  he  had  been  asleep 
for  a  definite  period  of  time,  have  shown  how  great  are  the  differences  in  the 
soundness  with  which  different  persons  sleep.  The  height  of  the  waking 
threshold  during  a  certain  period  of  sleep  may  be  used  as  the  measure  of  the 
soundness  of  sleep.  If  now  these  waking  threshold  values  are  expressed  in 
curves,  sleep  curves  for  the  different  periods  of  the  experiment  may  be  obtained 
which  indicate  graphically  the  more  or  less  rapid  rise  to  the  maximum  soundness 
of  sleep  and  the  gradual  fall  up  to  the  time  of  awaking  (Kohlschiitter). 

With  good  normal  sleep  the  summits  of  the  curves  are  higher  and  are  more 
rapidly  attained  than  with  poor  sleep,  in  which  the  curve  expresses  an  insuffi- 
cient soundness  of  sleep  during  the  first  hours  and  then  runs  along  at  about  the 
same  moderate  height,  instead  of  falling  in  the  morning  as  an  expression  of  the 
awakening  in  a  refreshed  condition.  Under  the  influence  of  an  hypnotic,  for 
example,  of  paraldehyde,  a  light  and  insufficient  sleep  is  induced  which  approaches 
the  type  of  normal  sleep. 


MODE  OF  ACTION  OF  HYPNOTICS 


87 


In  Fig.  7  the  curves  obtained  by  Michelson  by  observations,  under  as  con' 
stant  conditions  as  possible,  on  afternoon  sleep  lasting  several  hours,  with  and 
without  paraldehyde,  are  given  as  evidence  of  this.  The  two  curves,  Ila  and  lib, 
which  were  obtained  under  the  influence  of  paraldehyde,  in  comparison  with 
curve  7,  the  curve  of  normal  light  afternoon  sleep,  show  a  much  more  pronounced 
soundness  of  sleep,  as  they  rise  much  more  sharply  and  thus  resemble  the 
type  of  normal  sleep  during  the  night. 

The  results  of  investigations  of  simple  psychical  reactions  in 
individuals,  who  had  taken  some  hypnotic, 
are  in  complete  agreement  with  this  demon- 
stration that  these  hypnotics  diminish  the 
efficiency  of  waking  stimuli,  for  Krdpelin 
and  his  collaborators  have  shown  that  an 
impairment  in  the  perception  of  external 
stimuli  is  a  characteristic  effect  of  the  hyp- 
notics (paraldehyde,  chloral  hydrate,  trional), 
which  is  also  produced  by  alcohol.  Small 
doses  of  morphine  do  not  produce  this  effect 
on  the  function  of  perception,  and  conse- 
quently they  are  not  to  be  considered  as 
true  hypnotics. 

In  addition,  the  different  hypnotics, 
although  in  very  varying  degrees,  also  ren- 
der more  difficult  the  initiation  of  motor 
nervous  impulses.  While  paraldehyde  and 
particularly  alcohol  impair  motor  functions 
only  after  large  doses,  and  in  smaller  doses 
act  as  motor  stimulants,  chloral  hydrate 
and  trional,  from  the  very  start,  in  addi- 
tion to  impairing  the  perception  of  sensory 
impressions,  show  a  tendency  to  produce  a 
quieting  of  the  motor  functions  (Hdnel). 
Consequently  these  latter  have  the  power  of 
producing  a  pure  hypnotic  effect  without 
any  disturbing  symptoms  of  intoxication, 
while  alcohol  may  only  in  a  limited  sense  be 
described  as  a  hypnotic,  for  the  primary  motor  Jg^^ 
excitement,  caused  by  it  in  many  individuals,  wise  similar. 
produces  waking  stimuli  and  thus  prevents  the  falling  asleep. 


A 

A 

:    \ 

•      : 

•       i 

K 

i 

;  \ 

i    N 

i 

\ 

I 

fn 

\ 

"\ 

i  / 

\ 

\ 

:   / 

\ 

\ 

';/ 

.Ma 

\ 

V 

V     1 

\ 

N  / 

s 

V 

' 

PlG.  7._7>  curve  indicating 


IMPORTANCE   OF    THE   BATE    AT   WHICH    HYPNOTICS    ARE   ABSORBED    AND    ELIMINATED 

This  cutting  out  of  external  stimuli  by  the  hypnotics  produces  the  essen- 
tial conditions  for  the  development  of  sleep.  As  in  neurasthenics  the  inability 
to  fall  asleep,  except  late  and  with  great  difficulty,  is  often  the  chief  disturbing 
symptom,  in  these  cases  the  most  important  desideratum  is  to  deepen  the  sleep 
at  the  very  start.  Consequently,  the  readily  absorbable  hypnotics,  chloral  hydrate, 
paraldehyde,  and  the  like,  are  the  best  means  of  helping  such  patients  to  fall 
asleep.  With  other  forms  of  disturbed  sleep,  for  example,  in  the  typical  disturb- 
ance of  sleep  commonly  met  with  in  the  aged,  the  patient  falls  asleep  easily 


88     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

enough,  but  soon  after  wakes  up  again,  and  then  cannot  sleep  again.  With 
insomnia  of  this  type  hypnotics  possessing  a  more  lasting  action  are  indicated, 
for  example,  trional,  which  Hand  was  able  to  demonstrate  caused  a  diminution 
in  the  power  of  perception  which  persisted  into  the  following  day. 

In  general  it  is  essential  for  hypnotics  that  their  action  be  rapidly 
produced  and  persist  for  a  sufficient  period.  Both  of  these  desiderata 
will  be  best  accomplished  by  substances  which  are  soluble  in  water, 
which  distribute  themselves  equally  in  the  stomach  contents,  and 
which,  after  gradual  passage  into  the  intestine,  are  gradually  absorbed. 
At  the  same  time  hypnotics  must  not  be  excreted  or  destroyed  too 
rapidly,  while,  on  the  other  hand,  a  too  slow  excretion  or  destruction 
is  also  undesirable,  because  under  these  conditions  the  effects  would 
persist  on  the  following  day,  as  has  often  been  observed  after  the 
administration  of  sulphonal  and  trional,  as  also  after  veronal. 

FREEDOM  FROM  HARMFUL  SIDE  ACTIONS. — Above  all,  however,  all 
hypnotics  should,  in  therapeutic  doses,  produce  no  dangerous  side 
effects  on  the  circulation,  respiration,  or  metabolism,  and  also  should 
not  disturb  the  stomach.  With  the  augmentation  or  frequent  repetition 
of  the  dose,  naturally  all  hypnotics  are  dangerous.  In  the  presence 
of  an  especial  individual  susceptibility  or  of  pathological  conditions, — 
e.g.,  cardiac  or  pulmonary  disease, — these  side  actions,  especially  in  the 
case  of  the  more  powerful  hypnotics,  may  be  produced  even  by  the 
doses  which  are  necessary  in  order  to  produce  sleep.  This  is  the  case, 
however,  to  an  even  greater  degree  with  those  larger  doses  of  hypnotics 
which  are  employed  in  conditions  of  psychic  excitation,  with  the  object 
of  exerting  a  sedative  effect  on  the  cerebral  motor  centres,  or  which 
are  used  as  antidotes  in  poisoning  by  convulsant  poisons,  or  in  tetanus, 
etc.,  in  order  to  depress  the  excitability  of  the  spinal  cord. 

BIBLIOGRAPHY 

Hanel:  Krapelin's  psychophysiche  Arbeiten,  1897,  vol.  2,  No.  2. 
Kohlschutter:    Ztschr.  f.  rat.  Med.,  1863,  vol.  17. 
Koppen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  29,  p.  327. 
Michelson:  Krapelin's  psychophysiche  Arbeiten  u.  Diss.  Dorpat,  1891. 
Monninghoff  u.  Piespergen:  Ztschr.  f.  Biol.,  1883,  vol.  19. 

CHLORAL  HYDRATE 

Chloral  hydrate  is  the  member  of  this  group  which  has  been  longest 
in  use.  It  occurs  in  the  form  of  dry  transparent  crystals  with  an 
irritating  odor  and  a  mildly  bitter  and  pungent  taste.  It  is  very 
soluble  in  water,  alcohol,  and  ether,  and  is  quite  hygroscopic.  Con- 
centrated solutions  strongly  irritate  the  mucous  membranes,  and 
consequently  this  drug  should  always  be  administered  sufficiently 
diluted  and  never  in  solid  form,  otherwise  its  irritating  action  on 
the  stomach  mucous  membrane  may  cause  discomfort. 

Chloral  hydrate  is  formed  of  chloral  and  one  molecule  of  water.  Chloral 
itself,  OC13.COH,  or  trichloracetaldehyde,  the  aldehyde  of  trichloracetic  acid,  is  a 
colorless  corrosive  fluid.  It  was  first  prepared  by  Liebig,  in  1832,  by  the  action 


CHLORAL  HYDRATE  89 

of  chlorine  on  ethyl  alcohol,  the  method  still  used  in  its  manufacture.  Chloral 
unites  with  water  with  the  development  of  heat  to  form  chloral  hydrate,  the 
equation  of  the  reaction  being  CC1S.COH  +  H2O  =  CC13.CH  ( OH )  2.  According  to 
Victor  Meyer  and  Caro,  this  water  is  not  combined  as  water  of  crystallization, 
but  is  a  dihydroxyl  combination,  for,  in  contradistinction  to  chloral,  it  no  longer 
contains  an  aldehyde  radical. 

The  reaction  between  chloral  hydrate  and  aqueous  solutions  of 
the  alkalies  is  of  particular  interest.  Chloral  is  decomposed  by  the 
alkalies,  with  the  formation  of  chloroform  and  formic  acid,  a  reaction 
which  takes  place  at  ordinary  temperatures  and  still  more  readily 
under  the  influence  of  heat,  according  to  the  following  formula: 

CC13.COH  +  KOH  =  CHC13  +  HCOOK. 

It  is  this  decomposition  of  chloral  with  the  formation  of  chloro- 
form which  in  1869  suggested  to  Liebreich  the  hypothesis  that  chloral 
hydrate  was  gradually  broken  up  by  the  alkaline  reacting  blood,  with 
the  formation  of  chloroform,  and  that  thus  a  continuous  chloroform 
effect  would  be  exerted  in  the  body.  While  this  hypothesis  has  been 
shown  to  be  incorrect,  it  was  responsible  for  the  introduction  into 
therapeutics  of  the  first  synthetically  formed  hypnotic. 

As  a  matter  of  fact,  chloral  hydrate  is  not  decomposed  in  the  body, 
but  produces  its  effects  as  unchanged  chloral.  This  is  shown  by  the 
fact  that  almost  all  of  it  is  excreted  undecomposed  but  in  combination 
with  various  substances.  Furthermore,  the  carbonate  alkalinity  of 
the  blood  is  not  sufficient  to  decompose  chloral  hydrate  at  the  body 
temperature  in  the  manner  in  which  this  decomposition  occurs  in  the 
test-tube. 

Moreover,  in  case  such  a  decomposition  of  chloral  hydrate  took 
place  in  the  body  to  any  recognizable  extent,  chloroform  would  neces- 
sarily be  present  in  the  expired  air,  but,  according  to  Hammarsten, 
Hermann,  and  Tomascevicz,  even  the  most  delicate  reagents  fail  to 
indicate  its  presence  here.  Chloroform  is  also  not  present  in  the  blood 
of  chloralized  animals,  although  chloral  hydrate  may  be  demonstrated 
therein  in  all  periods  of  the  narcosis  (Archangelsky). 

FATE  IN  THE  BODY 

Chloral  hydrate,  as  already  mentioned,  is  almost  completely  excreted  in  the 
urine,  chiefly  as  trichlorethylglycuronic  acid  or  urochloralic  acid,  and  only  in 
very  small  amounts  as  unchanged  chloral  hydrate.  A  very  small  portion  is 
retained  in  the  body  for  a  considerable  time  and  is  gradually  decomposed, 
with  a  resulting  increase  of  the  chlorides  in  the  urine,  which  persists  for  some 
time  (Liebreich,  1869). 

During  its  transformation  into  urochloralic  acid,  which  is  pharmacologically 
inert,  chloral,  which  is  a  halogen  substituted  aldehyde,  is  first  reduced  to  an 
alcohol  before  combining  with  glycuronic  acid.  The  combination  of  chloral  with 
glycuronic  acid  is  thus  seen  to  be  a  process  similar  to  that  by  which  numerous 
substances  of  the  aliphatic  series,  and  particularly  aromatic  substances,  are  dis- 
toxicated  ( tfusculus  u.  Mering,  Kiilz ) . 

This  combination  of  drugs  with  glycuronic  acid  is  of  some  importance  to 
the  practising  physician,  inasmuch  as  some  of  these  combinations,  for  example 
urochloralic  acid,  reduce  cupric  oxide  in  alkaline  solutions.  Urine  containing 


90     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

such  combined  glycuronic  acid  may  consequently  give  a  reaction  which  might 
lead  to  an  erroneous  conclusion  that  they  contain  sugar.  Glycuronic  acid  is, 
however,  not  fermented  by  yeast  and  in  combination  polarizes  light  to  the  left. 

THERAPEUTIC  EMPLOYMENT. — As  a  rule,  in  doses  of  1.0  gin.  for  an 
adult,  chloral  hydrate  produces  sleep,  and  in  doses  of  2.0-3.0  gm. 
causes  profound  sleep.  As  a  result  of  its  ready  solubility  and  absorba- 
bility, sleep  usually  follows  very  promptly  on  its  administration,  lasts 
about  8  hours,  and  is  usually  not  followed  by  any  after-effects.  In 
some  individuals  exanthematous  eruptions  are  caused  by  chloral,  while 
in  others  the  local  irritating  effect  in  the  stomach  causes  gastric  dis- 
turbance. Idiosyncrasies  toward  it  may  also  be  met  with,  as  a  result 
of  which  it  fails  of  producing  hypnotic  effects  and,  in  place  of  so  doing, 
even  causes  considerable  excitation.  Consequently,  the  first  dose  of 
this  drug  should  not  exceed  1.0  gm.  (Stintzing). 

Much  larger  doses,  exceeding  even  the  ordinary  maximum  dose  of 
3.0  gm.,  may  be  necessary  to  produce  the  desired  sedative  effects 
in  conditions  of  mental  excitement,  in  delirium  tremens,  or  in  the 
convulsions  of  eclampsia,  tetanus,  or  strychnine  poisoning.  With  such 
doses,  however,  the  dangerous  actions  of  this  drug  may  manifest 
themselves  to  a  very  appreciable  degree. 

These  HARMFUL  ACTIONS  OF  CHLORAL  HYDRATE  consist  chiefly  in 
harmful  effects  on  the  heart  and  on  the  vessels.  Inasmuch  as  its 
actions,  in  general  terms,  resemble  a  protracted  mild  chloroform  action, 
the  vasomotor  centres  and  the  heart  are  depressed  relatively  early, 
juet  as  is  the  case  with  chloroform.  In  patients  with  fatty  hearts, 
myocardial  degeneration,  arteriosclerosis,  etc.,  these  dangerous  actions 
may  manifest  themselves  even  after  ordinary  hypnotic  doses,  and 
after  large  doses  sudden  heart  death  may  occur  in  such  patients.  Like 
chloroform,  chloral  hydrate,  even  in  therapeutic  dosage,  may  cause 
a  fall  in  the  blood-pressure  as  a  result  of  a  commencing  vasomotor 
depression,  and  the  pulse  may  become  soft  with  increased  amplitude. 
The  differences  between  the  therapeutically  effective  concentrations  in 
the  blood  and  the  concentrations  which  depress  the  circulation  are  not 
great.  In  ArchangelsJcy's  experiments  the  chloral  concentration  of 
the  blood  of  dogs  lying  in  profound  sleep  lay  between  0.03  and  0.05 
per  cent.,  while  when  this  concentration  reached  0.056  per  cent,  the 
blood-pressure  had  fallen  to  one-half  of  its  original  height,  and  with 
a  concentration  of  0.07  per  cent,  cessation  of  respiration  occurred. 
[Clinical  experience  with  this  drug  indicates  very  clearly  that  the 
dangers  of  harmful  depression  of  the  circulation,  when  chloral  is  cor- 
rectly used,  have  been  greatly  over-estimated.  The  figures  quoted  above 
of  a  concentration  of  0.03-0.05  per  cent,  in  the  blood,  in  no  way 
correspond  to  the  concentrations  which  can  be  produced  by  any 
ordinary  doses. — TR.] 

Relaxation  of  the  vessels  results  in  a  slowing  up  of  the  blood  flow 
throughout  the  body,  and,  if  this  lasts  for  any  considerable  time,  in 


CHLORAL  HYDRATE  91 

patients  with  respiratory  disturbance  it  may  lead  to  cyanosis  and  even 
oedema  of  the  lungs,  while,  in  addition,  the  decided  direct  depression 
of  the  respiratory  centre  produced  by  chloral  hydrate  warns  one  to 
exercise  caution  in  its  use  in  such  patients. 

With  continued  use  there  is  danger  of  habituation.  Another  reason 
why  abuse  of  this  drug  is  dangerous  is  that  chloral  hydrate  may  cause 
a  parenchymatous  degeneration  of  certain  of  the  important  organs, 
in  which  particular  its  effect  is  similar  to  that  of  prolonged  chloroform 
anaesthesia. 

When  this  occurs,  the  decomposition  of  proteids  is  augmented,  just  as 
occurs  in  phosphorus  poisoning.  However,  the  breaking  down  of  the  proteids 
does  not  proceed  to  the  normal  final  stages,  but  stops  with  the  formation  of 
some  more  complicated  intermediate  decomposition  products,  whose  nature  is 
still  unknown  but  which  are  probably  substances  resembling  the  peptones 
(Harnack). 

TOXICOLOGY. — Especially  when  first  introduced  into  practice 
numerous  acute  medicinal  poisonings  by  chloral  hydrate  resulted  from 
its  administration  in  too  large  doses,  and,  as  a«  result  of  its  continued 
use  as  a  sedative,  cases  of  chronic  chloral  habit  developed,  particularly 
in  insane  asylums.  To-day  medicinal  poisonings  have  become  far  less 
frequent,  but  it  is  frequently  employed  for  suicidal  purposes.  Cases 
of  fatal  poisonings  have  been  observed  after  doses  not  exceeding 
4.0  gms. 

ACUTE  POISONING. — The  symptoms  of  acute  poisoning  correspond 
in  general  with  those  of  too  deep  anaesthesia  and  coma,  which  have 
already  been  described  in  connection  with  poisoning  by  other  narcotics. 
In  these  cases  the  symptoms  of  insufficient  respiration  and  marked 
impairment  of  the  circulation  develop  early  and  the  body  temperature 
falls.  If  the  drug  be  very  rapidly  absorbed,  death  may  ensue  very 
quickly  as  a  result  of  a  direct  paralytic  effect  on  the  heart,  and  the 
patient  may  suddenly  collapse.  When  the  absorption  has  taken  place 
more  gradually,  coma  and  complete  anaesthesia  with  abolition  of  the 
reflexes  develop,  and  death  results  from  cessation  of  the  respiration, 
the  heart  action  also  being  extremely  feeble.  In  contrast  to  the  usual 
behavior  of  the  pupils  in  morphine  poisoning,  they  are  widely  dilated 
in  chloral  poisoning,  and,  with  equally  deep  coma,  the  circulation  is 
much  more  markedly  depressed  by  chloral  hydrate,  while  the  respira- 
tion remains  relatively  good  much  longer  than  is  the  case  in  morphine 
poisoning,  in  which  the  respiration  is  alarmingly  depressed  before  the 
circulation  is  markedly  affected. 

The    TREATMENT    OF    ACUTE    CHLORAL    POISONING    Consists    first    in 

removing  the  poison  by  washing  out  the  stomach.  Emetics  cannot  be 
used  for  this  purpose,  for  they  will  necessarily  fail  to  act,  on  account 
of  the  depression  of  all  reflexes,  including  those  which  bring  about 
emesis.  In  severe  poisoning  artificial  respiration  must  be  instituted. 
As  long  as  this  is  not  necessary  the  effort  is  made  to  maintain  the 


92     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

functions  of  the  vasomotor  and  respiratory  centres  by  various  stimu- 
lating agents.  For  this  purpose  one  uses,  as  in  other  narcotic  poison- 
ings, sensory  stimuli,  subcutaneous  injections  of  solutions  of  caffeine, 
preparations  of  camphor  and  of  atropine.  [Caffeine,  in  the  form  of 
strong  hot  coffee  by  mouth  and  by  rectum,  is  used  almost  as  routine, 
Strychnine  subcutaneously  appears  also  to  be  of  distinct  value,  and 
epinephrin  intramuscularly  or  intravenously,  as  also  heat,  certainly 
appears  to  be  indicated. — TR.] 

CHRONIC  POISONING. — In  chronic  chloral  poisoning  disturbances 
of  the  digestive  organs  of  most  various  nature,  as  well  as  vasomotor 
and  psychical  disturbances,  occur.  Affections  of  the  skin  are  also  very 
common.  In  general,  the  clinical  picture  resembles  that  of  chronic 
morphinism.  When  the  attempt  is  made  to  give  up  the  drug,  various 
uncomfortable  symptoms  and  disturbing  conditions  develop,  among 
them  great  nervousness,  anxiety,  and  insomnia. 

BIBLIOGRAPHY 

Archangelsky :  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46. 

Hammarsten,  cited  from  Hermann:      Lehrb.  d.  exp.  Toxikologie,  Berlin,   1874, 

p.  271. 

Harnack  u.  Remertz:  Fortschr.  d.  Med.,  1893,  vol.  11,  No.  7. 
Kiilz,  E.:    Pfliiger's  Arch.,   1882,  vol.  28,  p.  506. 
Liebreich:  Das  Chloralhydrat  ein  neues  Hypnoticum  und  Anaestheticum,  Berlin, 

1869. 

Musculus  u.  Mering:  Bericht  d.  Deutsch.  chem.  Gesellsch.,  1875,  vol.  8,  p.  640. 
v.  Mering:   Zeitschr.  f.  physiol.  Chem.,  1882,  vol.  6,  p.  480. 
Stintzing;  Pentzoldt  u,  Stintzing's  Handb.  d.  spez.  Therap. 

OTHER  HYPNOTICS  OF  THIS  GROUP 

The  various  disadvantages  of  chloral  hydrate  soon  made  it  desirable 
to  search  for  substitutes  with  similar  hypnotic  action  unaccompanied 
by  the  undesirable  side  actions,  and,  as  a  result,  the  number  of  hyp- 
notics of  the  alcohol  group,  which  have  been  introduced  and  which 
are  still  widely  used,  has  become  extremely  large.  This  is  in  itself 
evidence  that  none  of  these  hypnotics  is  ideal,  possessing  all  the  proper- 
ties wished  for.  With  some,  the  disagreeable  taste  and  odor, — e.g., 
paraldehyde, — with  others,  unfavorable  behavior  in  respect  to  absorp- 
tion and  excretion, — e.g.,  sulphonal, — are  unavoidable  drawbacks.  Still 
others  possess  the  disadvantage  that  when  repeatedly  administered 
habituation  readily  develops,  while  with  others  harmful  side  actions 
occur  when  they  are  used  continually. 

On  the  other  hand,  the  different  types  of  insomnia  and  the  variable 
individual  susceptibility  toward  the  different  drugs  are  responsible 
for  the  practical  demand  for  numerous  hypnotics,  for  the  undesirable 
side  actions  of  the  different  hypnotics  are  of  greater  or  less  moment 
according  to  varying  pathological  conditions  in  which  they  may  be 
employed.  Furthermore,  the  harmful  effects  of  the  continued  use  of 
one  drug  often  render  it  necessary  that  a  change  be  made  from  one 
hypnotic  to  another. 


CHLORAL  DERIVATIVES  93 

If  one  surveys  the  whole  group  of  hypnotics  which  have  been  intro- 
duced since  chloral  hydrate,  the  empiric  rule  may  be  formulated  that 
those  hypnotics  which  contain  no  halogen,  in  general,  affect  the  heart 
and  the  vessels  less  than  do  those  containing  these  elements.  This 
conclusion  corresponds  entirely  with  that  formed  from  practical  experi- 
ence with  the  general  anaesthetics.  As  a  result,  with  the  halogen-free 
hypnotics  there  is  a  greater  difference  between  those  doses  sufficient  to 
produce  sleep  and  those  which  unfavorably  affect  the  circulation  and 
respiration. 

CHLORALAMIDE. — Substitutes  for  chloral  hydrate,  which  contain  the 
molecule  of  this  uncommonly  active  substance  in  combination  and 
from  which  the  chloral  may  be  set  free  in  the  body,  will  consequently 
possess  no  essential  advantages  over  chloral  hydrate  itself.  This  holds 
true  for  the  widely  used  chloralamide,  which  is  formed  by  the  union 
of  chloral  with  formalin  according  to  the  following  formula : 

CC13.CHO  +  H.CONH2  =  CC13CH(OH)N(CHO)H. 

This  drug  occurs  as  crystals,  soluble  in  water  in  the  proportion  of  one  part 
in  20,  which  are  not  irritating  and  which  possess  a  slightly  bitter  taste.  The 
absence  of  irritating  action  in  the  stomach  and  the  slight  taste  are  the  chief 
advantages  which  it  possesses  as  compared  with  chloral  hydrate,  but  the  effective 
hypnotic  dose  is  one  and  one  half  times  as  large  as  that  of  chloral.  Sleep  is 
usually  produced  from  %  to  2  hours  after  its  administration. 

Dormiol. — Another  combination  of  chloral  with  dimethylethylcar- 
binol  (amylene  hydrate),  dormiol,  has  recently  been  introduced  and 
recommended  (Fuchs  u.  Koch).  This  amylene  chloral  is  an  oily 
water-clear  fluid  with  a  smell  resembling  that  of  camphor.  It  may  be 
administered  in  gelatin  capsules  containing  0.5  gm.  In  dosage  of  0.5- 
1.5  gm.  it  induces  sleep  after  y2  to  1  hour,  which  is  not  accompanied 
by  harmful  side  effects  (Peters).  [Later  experience  with  this  drug 
has  shown  that  this  claimed  freedom  from  harmful  side  actions  has 
not  been  justified. — TR.] 

Isopral. — Another  hypnotic  containing  chlorine,  isopral,  or  trichloriso- 
propyl  alcohol  (Impens),  has  been  rather  widely  used.  This  drug  is  readily 
soluble  and  easily  absorbed,  sleep  usually  following  in  14  to  %  hour  after  its 
administration  in  dosage  of  0.5  to  1.0  gm.  (Urstein) .  Although  its  toxic  action 
on  the  heart  is  slight,  experiments  on  animals  show  that  it,  too,  depresses  the 
blood-pressure.  Caution  is  consequently  necessary  in  connection  with  its  use 
in  the  presence  of  circulatory  disease.  [Hatcher  has  demonstrated  that  the  claims 
made  for  its  relatively  slight  toxicity  as  compared  with  chloral  are  not 
correct. — TR.] 

BIBLIOGRAPHY 

Fuchs  u.  Koch:  Munchn.  med.  Woch.,  1898,  No.  37. 
Impens:   Therap.  Monatsh.,  1903,  pp.  469  and  533. 
Peters:  Mtinchn.  med.  Woch.,  1900,  No.  14. 
Urstein:  Therapie  d.  Gegenwart,  1904,  p.  64. 

PARALDEHYDE. — The  first  hypnotic  of  this  group  which  is  really 
free  from  harmful  side  actions  on  the  functions  of  other  organs  was 
introduced  by  Cervello  in  1883.  [This  freedom  from  harmful  actions 


94     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

is  only  a  relative  one. — TR.]  This  is  a  polymeric  modification  of  the 
common  aldehyde  CH3.COH,  three  molecules  of  which  are  combined 
in  it. 

It  is  a  clear,  colorless,  readily  inflammable  fluid  with  a  characteristic 
odor  and  burning  taste,  rather  soluble  in  water  (1  to  8),  and  easily  absorbed, 
so  that  sleep  quickly  follows  its  administration,  often  within  10  to  15  minutes. 
It  is  a  powerful  narcotic,  with  little  harmful  action  on  the  respiration,  circu- 
lation, or  metabolism.  In  essential  insomnia,  doses  of  about  3.0  gm.  are  usually 
efficacious,  and  even  with  long-continued  employment  of  such  doses  no  dangerous 
side  effects  result.  [This  statement  is  not  strictly  correct,  for  the  literature 
contains  more  than  one  reference  proving  that  the  contrary  may  at  times  be 
true. — TB.]  In  extreme  insomnia  the  dosage  must  be  increased  up  to  4-6  gm., 
but  much  larger  doses  (even  as  much  as  30-60  gm. )  have  been  taken  without 
dangerous  results  (Bumke1).  According  to  many  observers,  habituation  to 
paraldehyde  is  readily  acquired,  just  as  is  the  case  with  alcohol,  but  this  cer- 
tainly is  not  always  the  case  (Bumke?  Stintzing).  The  only  disadvantage  of 
this  relatively  harmless  and  efficient  drug  is  its  disagreeable  taste,  which  is  best 
disguised  by  red  wine  or  tea,  and  its  odor,  which  resembles  that  of  fusel  oil, 
and  which,  on  account  of  its  slow  excretion  by  the  lungs,  is  apparent  in  the 
breath  even  on  the  day  following  its  administration. 

BIBLIOGRAPHY 

1  Bumke:  Miinchn.  med.  Woch.,  1902,  No.  47,  p.  1958. 

*  Bumke:  Monatschrift  f.  Psychiatr.  u.  Neurol.,  vol.  12. 

Cervello:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  16,  p.  265. 

Stintzing:  Penzoldt-Stintzing's  Handb.  d.  Ther.  d.  inn.  Krankh.,  vol.  5,  p.  396. 

Amylene  hydrate,  dimethylethyl  carbinol,  is  a  tertiary  alcohol  of 
the  amyl  series  — 


It  is  a  colorless,  oily,  rather  soluble  (1  to  8)  fluid,  with  a  disagreeable  odor 
resembling  that  of  paraldehyde.  In  respect  to  the  intensity  of  its  hypnotic  power 
it  lies  between  chloral  hydrate  and  paraldehyde, — 1.0  gm.  chloral  hydrate  =  2.0 
gm.  amylene  hydrate  =  3.0  gm.  paraldehyde.  Like  other  amyl  compounds,  such 
as  the  so-called  fusel  oils,  which  in  general  exert  a  more  powerful  effect  on 
the  nervous  system  than  the  ethyl  combinations, — e.g.,  ethyl  alcohol, — amylene 
hydrate  also  produces  more  marked  depression  of  the  circulation  than  does 
paraldehyde.  However,  in  this  respect  amylene  hydrate  has  the  reputation 
of  being  less  open  to  objection  than  choral.  The  usual  dose  is  2.0  gm.,  4.0  gm. 
being  the  maximal  single  dose.  It  may  be  administered  in  gelatin  capsules  or  in 
solution  by  mouth  or  by  rectum.  This  drug  possesses  the  disadvantage  that 
even  hypnotic  doses  may  cause  a  condition  resembling  alcoholic  intoxication,  as 
it  strongly  excites  the  motor  centres,  so  that  in  animals  restlessness  or  even 
severe  convulsions  may  result  from  its  administration  in  poisonous  doses 
(Harnack  u.  Hermann  Meyer). 

Urethan  is  satisfactory  in  respect  to  its  freedom  from  disagreeable 
side  actions,  as  well  as  in  respect  to  its  solubility,  taste,  and  odor.  In 
experiments  on  animals  it  shows  itself  to  be  an  extremely  good  hyp- 
notic which  even  in  strongly  hypnotic  doses  does  not  impair  the  heart 
action  at  all  (Schmiedeberg).  Its  hypnotic  power  in  man  is,  however, 
weak  and  uncertain,  so  that  it  has  not  been  able  to  establish  itself 
as  useful. 


SULPHONAL  AND  TRIONAL  95 

Chemically  it  is  the  ethyl  ester  of  carbaminic  acid  — 

/NH2 
\OGH. 

It  occurs  as  colorless  and  odorless  crystals  readily  soluble  in  water,  with  a  salty 
taste.  For  adults  the  dose  is  2.0-4.0  gm. 

Hedonal.  —  Under  the  name  of  Hedonal,  Dreser  has  introduced  another  hyp- 
notic belonging  chemically  to  the  same  class  as  urethan.  In  it  the  ethyl  radical  is 
replaced  by  a  methylpropylcarbinol  radical 

/NH2 


It  occurs  as  colorless  crystals,  soluble  with  difficulty  in  water,  and  with  a 
somewhat  disagreeable  taste  resembling  that  of  peppermint.  It  is  best  adminis- 
tered in  powdered  form  in  wafers,  and,  in  doses  of  from  1.0-2.0  gm.,  produces 
a  much  more  powerful  hypnotic  effect  than  ethyl  urethan  (urethan).  This  drug 
has  been  highly  praised  by  some  authors,  but,  according  to  E.  Miiller,  it  appears 
to  be  unreliable  in  cases  of  slight  insomnia  and  often  to  fail  even  when  larger 
doses  are  given.  It  appears  to  have  no  dangerous  side  actions,  but  at  times  a 
pronounced  polyuria  caused  by  it  interferes  with  the  sleep.  It  also  appears 
that  habituation  readily  occurs  with  both  hedonal  and  urethan. 

BIBLIOGRAPHY 

Dreser:  Versamml.  d.  Naturforscher  und  Arzte,  1899. 
Harnack  u.  Herm.  Meyer:   Ztschr.  f.  klin.  Med.,  1894,  vol.  24,  p.  374. 
Miiller,  E.:  Miinchn.  med.  Woch.,  1901,  No.  10,  p.  383,  here  compl.  lit. 
Schmiedeberg;  Arch.  f.  exp.  Pathol.  u.  Pharm.,  1885,  vol.  20,  p.  203. 

SULPHONAL  and  TRIONAL  have  apparently  been  more  widely  em- 
ployed as  hypnotics  than  almost  any  other  drugs.  The  hypnotic  actions 
of  these  disulphones  was  accidentally  discovered  by  Baumann  and 
East  in  certain  physiological  experiments  instituted  with  another 
object. 

Chemically  sulphonal  (sulphonmethane,  U.S.P.)  is  diethyl- 
sulphonedimethylmethane,  (CH3)2  =  C  =(SO2C2H5)2,  and  occurs1  as 
colorless,  tasteless  crystals,  very  slightly  soluble  in  cold  water  (1  to 
500).  When  administered  as  a  powder  in  doses  of  1.0  to  2.0  gm. 
(4.0  gm.  [?  TR.]  maximal  single  dose)  together  with  a  sufficient  quan- 
tity of  warm  fluid,  sleep  usually  results  after  the  lapse  of  1-2  hours. 
On  account  of  its  relative  insolubility,  its  effects  are  produced  not 
only  slower  than  is  the  case  with  other  hypnotics,  but  they  last  longer, 
on  account  of  the  slowness  with  which  it  is  decomposed  and  excreted. 
After  waking  there  is  slight  dizziness,  and  on  the  following  day  the 
patient  is  often  drowsy. 

Trional  and  tetronal  are  analogous  substances,  in  which  ethyl 
radicals  replace  one  or  both  of  the  methyl  groups  of  sulphonal  and 
which  are  more  active  than  their  mother  substance. 

TRIONAL  (diethylsulphonemethylethylmethane),  or  sulphonethyl- 
methane,  is  at  present  preferred  by  most  authorities'  to  sulphonal, 
because,  as  it  is  more  soluble  than  sulphonal,  sleep  is  more  rapidly 


96     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

induced,  and  because  the  factors  determining  its  decomposition  and 
elimination  are  more  favorable  (Morro).  Doses  of  1.0-1.5  gin.  cause 
sleep  after  y±  to  y2  hour.  4.0  gm.  [  ?  TE.]  is  the  maximal  single  dose. 

In  proper  doses  sulphonal  and  trional  produce  no  harmful  effects 
on  the  circulation,  respiration,  or  digestion.  After  larger  doses  or 
after  continued  use  of  small  doses,  however,  they  may  cause  poisoning, 
evidenced  by  disturbances  of  the  digestive  organs,  the  metabolism,  and 
the  central  nervous  system.  Single  doses  produce  such  symptoms 
of  poisoning  only  when  the  usual  dose  has  been  very  largely  exceeded. 
This  holds  true  especially  for  the  relatively  less  poisonous  trional 
(Robert}. 

Trional,  like  sulphonal,  often  produces  a  satisfactory  hypnotic  effect 
even  in  the  second  night,  this  after-effect  proving  that  a  certain  quan- 
tity of  the  drug  still  remains  in  the  body  in  a  form  which  is  still 
active.  The  harmful  effects  of  both  of  these  drugs  also  are  due  to  this 
persistent  after-effect,  the  danger  of  cumulation  being  greater  with  the 
less  readily  decomposed  sulphonal  than  it  is  with  trional.  The  majority 
of  the  numerous  cases  of  poisoning  produced  by  these  drugs,  which 
formerly  were  frequently  observed  as  a  result  of  their  careless 
employment  (especially  with  sulphonal),  occurred  when  they  were 
administered  during  too  long  a  period  (lit.  Friedlander,  v.  Taylor  and 
Sail). 

East  states  that  in  man  the  dosage  of  sulphonal  should  not  exceed 
2.0  gm.,  and  in  women,  who  are  much  more  readily  poisoned,  it  should 
not  exceed  1.0  gm.,  and  that,  when  used  for  a  long  time,  its  adminis- 
tration should  be  discontinued  in  periods  of  one  to  several  days.  With 
trional  also  daily  administration  is  not  permissible,  and  even  with 
men  the  doses  should  not  exceed  1.25  gm. 

In  SULPHONAL  POISONING  the  symptoms  consist  in  persisting  con- 
fusion, ataxia,  constipation,  vomiting,  and  abdominal  pain,  and  also 
in  symptoms  of  irritation  of  the  kidney,  albuminuria  and  nephritis. 
In  the  majority  of  cases  there  is  also  a  peculiar  decomposition  of  the 
hsemoglobin,  resulting  in  the  appearance  of  haematoporphyrin  in  the 
urine.  The  reddening  of  the  urine  thus  caused,  while  not  constant,  is  a 
very  frequent  symptom  of  sulphonal  or  trional  poisoning,  and,  as  this1 
symptom  is  often  one  of  the  first  to  develop,  it  may  serve  as  a  warning. 
Consequently,  whenever  these  drugs  are  continually  administered,  the 
urine  should  be  regularly  examined.  Thus  far  we  know  nothing  of 
the  manner  in  which  haematoporphyrinuria  is  produced.  It  may  be 
experimentally  produced  in  rabbits  but  not  in  dogs  (Neubauer). 

BIBLIOGRAPHY 

Baumann  u.  Kast:   Zeitschr.  f.  physiol.  Chemie,  1890,  vol.  14. 
Friedlander:   Therap.  Monatsh.,  1894,  pp.  183  and  370. 
Kast:  Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  31,  p.  69. 


VERONAL  GROUP  97 

Kast:  Berl.  klin.  Woch.  u.  Therap.  Monatshefte,  1888. 
Robert:   Lehrb.  d.  Intoxikationen,  2d  edition,  Stuttgart,  1906. 
v.  Mering:   Therap.  Monatsh.,  1896,  p.  421. 
Morro:   Deutsche  med.  Woch.,  1894,  No.  34  and  46. 
Neubauer :  Arch,  f .  exp.  Path.  u.  Pharm.,  1900,  vol.  43,  p.  456. 
v.  Taylor  u.  Sail:  neurol.  Zentralbl.,  1901,  No.  11,  p.  516. 

VERONAL. — Comparatively  recently,  diethylbarbituric  acid,  veronal, 
and  dipropylbarbituric  acid,  proponal,  have  been  introduced  as  hyp- 
notics and  have  very  rapidly  been  extensively  employed  (E.  Fischer 
and  v.  Mering). 

Veronal, 


occurs  as  a  crystalline  powder,  soluble  with  difficulty  in.  water,  and  with  a 
slightly  bitter  taste.  The  mean  hypnotic  dose  is  0.5  gm.,  but  with  women  doses 
of  0.25-0.3  gm.  are  often  sufficient.  As  far  as  may  be  judged  from  the  reports 
at  present  available,  it  is  a  reliable  and,  in  proper  dosage,  harmless  hypnotic. 
However,  it  appears  that  its  use  is  not  unattended  with  danger  in  case  its 
administration  is  too  quickly  repeated.  [At  least  two  fatal  cases  of  poisoning 
have  occurred  after  relatively  small  amounts  had  been  taken. — TB.]  It  is 
excreted  in  unaltered  form,  but  rather  slowly  (E.  Fischer  and  v.  Mering,  Aug. 
Hoffmann),  so  that  prolonged  action  and  rather  lasting  conditions  of  confusion 
have  often  been  observed.  Its  sodium  salt,  medinal,  is  more  soluble  in  water, 
and  consequently  may  at  times  be  preferred  to  veronal.  When  injected  subcu- 
taneously  into  animals,  from  45  to  90  per  cent,  of  the  amount  administered  is 
excreted  in  the  urine,  the  amount  thus  excreted  varying  with  the  size  of  the 
dose.  It  has  not  been  possible  experimentally  to  demonstrate  that  it  produce8 
any  well-marked  cumulative  effects  (Bachem.)  Following  too  large  doses  in  a 
number  of  cases,  sleep  lasting  for  days  has  already  been  observed.  [In  animals 
veronal  may  produce  degeneration  of  the  kidney. — TB.] 

Proponal  acts  more  rapidly  than  veronal,  and  0.35  gm.  appears  to  produce 
about  the  same  effect  as  0.5  gm.  of  veronal  ( Romheld ) .  Ziehen  warns  against 
exceeding  the  dose  of  0.5  gm. 

Neuronal. — Still  another  hypnotic  is  neuronal,  bromdiethylacetamide, 
CBr(C2H6)oCONH2  (Fuchs  and  E.  Schultze).  This  is  a  powder,  soluble  with 
difficulty  in  water,  which  is  effective  in  doses  of  from  0.5-1.0  gm.  Up  to  1905 
there  were  no  reports  indicating  that  it  produces  any  harmful  side  effects  or 
cumulation  (Bleibtreu,  K.  Schultze). 

Bromural. — Krieger  and  v.  d.  Velden  have  reported  favorably  of  their 
experience  with  bromural,  2  monobrom-isovaleryl-urea,  in  doses  of  0.6-1.0  gm. 
in  the  form  of  tablets.  This  drug  acts  as  a  mild  hypnotic  and  useful  sedative, 
producing  its  effects  fairly  rapidly.  In  experiments  on  animals  a  deep  narcosis 
may  be  induced  by  this  drug  without  harmfully  affecting  the  circulation  or  the 
respiration. 

BIBLIOGRAPHY 

Bachem:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  228. 
Fischer,  E.,  u.  v.  Mering:  Med.  Klinik,  1905,  No.  52,  p.  1327. 
Fischer,  E.,  u.  v.  Mering:   Therapie  d.  Gegenw.,  1903. 
Fischer,  E.,  u.  v.  Mering:  Therapie  d.  Gegenw.,  1904. 
Fuchs  u.  E.  Schultze :   Miinchn.  med.  Woch.,  1905,  No.  50. 
Hoffmann,  Aug.:   Inaug.-Diss.,  Giessen,  1906. 
Krieger  u.  v.  d.  Velden:  Deutsche  med.  Woch.,  1907,  No.  6. 
Romheld:  Therapie  d.  Gegenw.,  1906,  p.  190. 
Schultze,  K. :  Therapie  der  Gegenw.,  1905,  p.  14. 
Ziehen:  Deutsche  med.  Woch.,  1908. 
7 


98     PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

THE    RELATIONSHIP    BETWEEN    CHEMICAL    CONSTITUTION 
AND   PHARMACOLOGICAL   ACTION 

In  this  section  only  those  members  of  the  alcohol  group  have  been 
discussed  which  have  been  widely  employed  as  anesthetics  or  hypnotics. 
There  is  a  very  much  larger  number  of  substances  of  the  alipathic 
series  which  possess  more  or  less  marked  pharmacological  actions  of 
this  nature,  and  consequently,  as  may  well  be  understood,  many 
attempts  have  been  made  to  determine  the  relation  between  the  con- 
stitution of  these  hydrocarbons,  alcohols,  aldehydes,  ketones,  sulphones, 
esters,  etc.,  and  their  pharmacological  actions.  As  a  result,  a  number 
of  laws  or  principles  have  been  discovered,  with  the  aid  of  which  it 
has  been  possible  to  make  certain  deductions  which  have  rendered 
possible  a  successful  search  for  new  active  substances. 

In  general,  substances  in  which  the  alkyl  radicals  are  attached  to  tertiary 
or  quaternary  carbon  atoms  are  more  active  than  the  analogous  combinations 
containing  the  carbon  combined  with  only  one  or  two  other  carbon  atoms.  For 
this  reason,  the  primary  alcohols  produce  less  narcotic  effect  than  the  secondary 
ones,  and  these  in  turn  less  than  the  tertiary  alcohols  (v.  Mering  and  Schnee- 
gans).  Further,  in  general  the  law  holds  good,  that  ethyl  groups,  if  attached 
ito  carbon,  endow  substances  with  more  pronounced  narcotic  properties  than  do 
methyl  groups  in  the  same  situation.  Thus,  for  example,  ethyl  alcohol  is  more 
strongly  narcotic  than  methyl  alcohol,  v.  Mering  and  Schneegans  have  found 
that  in  the  series  of  tertiary  alcohols 

CH3  \ 
OH  CH3  -C-OH 


trimethyl  carbinol,  dimethylethyl  carbinol,  and  triethyl  carbinol,  the  hypnotic 
action  increases  according  to  this  law,  the  hypnotic  dose  in  rabbits  for  these 
three  substances  being  respectively  4.0,  2.0,  and  1.0  gm.  Baumann  and  Kast 
have  shown  a  similar  relationship  between  the  narcotic  power  and  the  number 
of  the  ethyl  radicals  contained  in  the  molecules  of  the  members  of  the  sulphone 
series,  in  which  the  attachments  of  alkyl  radicals  to  the  sulphone  radicals  which 
are  attached  to  the  quaternary  carbon  appear  to  have  the  same  significance  as 
their  direct  attachment  to  the  carbon  atom. 
Sulphonal 

CH3\r/S02.C2H5 


is  consequently  approximately  as  active  as  dimethylsulphonediethylmethane 


The   analogous    substance   containing    only   methyl    groups,    dimethylsulphonedi- 
methylmethane, 

CH3\    /SO,.CH3 
s/^  \SOo.CHs 


is  inactive,  but,  on  the  other  hand,  trional,  which  contains  three  ethyl  radicals, 
is  more  active  than  sulphonal,  while  tetronal,  diethylsulphonaldiethylmethane, 


C2H6/^\SO2.C2H5, 


CHEMICAL  CONSTITUTION;  PHARMACOLOGIC  ACTION  99 

which  contains  four  ethyl  groups,  is  still  more  active.  This  relationship  between 
the  activity  of  the  substance  and  the  number  of  ethyl  groups  holds  good,  how- 
ever, only  for  a  certain  intramolecular  arrangement  of  the  atoms,  such  as  is 
present  in  sulphonal.  Even  in  such  disulphones  as  contain  the  sulphone  radical 
attached  to  different  carbon  atoms,  as,  for  example,  in  ethylenediethylsulphone, 


the  ethyl  groups  no  longer  produce  these  effects    (  Baumann  and  East  )  . 

This  law,  therefore,  holds  good  only  within  certain  limits,  the  introduction 
of  other  groupings  into  the  molecule  lessening  the  importance  of  the  ethyl  radicals 
or  entirely  abolishing  it.  Notwithstanding  this,  the  deduction  that  the  com- 
bination of  ethyl  groups  with  a  tertiary  or  quaternary  carbon  atom  results  in 
especially  powerful  hypnotic  powers,  has  pointed  out  the  path  to  the  synthesis 
of  other  hypnotics,  —  for  example,  to  that  of  veronal  (  Fischer  u.  v.  Mering  )  . 

The  introduction  of  halogen  atoms  attached  directly  to  carbon  increases 
the  narcotic  power  of  substances  already  possessing  such  powers.  Thus,  the 
narcotic  effect  of  the  hydrocarbon  methane,  CH*,  is  extremely  slight,  but,  with  the 
successive  substitutions  of  chlorine  for  its  hydrogen  atoms,  its  narcotic  action  is 
augmented,  chloroform,  CHC13,  being  more  active  than  bichlormethane,  CH2C12, 
which  in  turn  is  more  active  than  methylchloride,  CH8C1.  However,  the  introduc- 
tion of  chlorine  atoms,  as  a  rule,  also  endows  the  substance  with  toxic  side 
actions  on  the  heart  and  vasomotor  centres,  a  fact  to  which  attention  has  already 
been  directed  in  connection  with  the  comparison  of  ether  with  chloroform,  and 
also  in  connection  with  the  comparison  of  chloral  hydrate  with  alcohol  and  the 
chlorine-free  substitutes  for  chloral  hydrate.  As  a  result  of  the  study  of  these 
relationships,  it  is  clearly  evident  that  not  only  the  intensity  of  the  narcotic 
actions  but  also  the  character  or  quality  of  pharmacological  actions  may  be 
changed  by  the  introduction  of  chlorine  atoms  (Kionka).  For  example,  the 
introduction  of  still  another  chlorine  atom  into  chloroform  transforms  this  sub- 
stance into  tetrachlormethane,  CC14,  which  is  a  convulsant  poison  (v.  Ley).  The 
strengthening  influence  of  the  introduction  of  the  halogens  may  also  be  demon- 
strated when  bromine  atoms  are  substituted  in  hydrocarbons  (Fuchs  u.  Schultze, 
v.  d.  Eeckout). 

The  narcotic  power  of  trichloracetic  acid  when  compared  with  that  of  the 
corresponding  aldehyde,  chloral,  is  very  slight.  This  will  serve  as  an  illustration 
of  the  general  law  that  the  introduction  of  acid  radicals  weakens  or  abolishes 
the  narcotic  activity  of  various  atom  groups, 

The  investigation  of  the  relationship  between  chemical  constitution 
and  pharmacological  action  in  the  alcohol  group  has  thus  led  to  the 
conclusion  that  the  entrance  of  certain  atoms  and  atom  groups  into 
certain  active  compounds  augments  or  weakens  their  activity.  There 
is  still  lacking,  however,  an  explanation  why  the  ethyl  groups,  for 
example,  increase  the  activity  of  the  substances  only  when  they  are 
introduced  into  substances;  of  certain  definite  configuration  and  do 
not  augment  the  activity  of  other  molecules  with  another  configuration. 
It  is  certain  that  the  ethyl  groups  themselves  do  not  independently  pro- 
duce these  effects,  for  those  substances  whose  activity  is  attributable  to 
the  ethyl  groups  —  such,  for  example,  as  the  disulphones  (Diehl)  or 
ethyl  alcohol  —  certainly  produce  their  effects  before,  and  not  after, 
they  have  been  decomposed.  The  ethyl  groups,  therefore,  do  not  pro- 
duce their  pharmacological  effects  after  they  have  been  split  off  from 
the  whole  complex.  If,  therefore,  the  number  of  them  present  in 
the  molecule  determines  the  degree  of  its  activity,  this  is  only  to  be 


100   PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

understood  on  the  assumption  that  the  entrance  of  the  ethyl  groups 
into  the  molecule  endows  it  with  certain  chemical  or  physical  proper- 
ties which  are  responsible  for  the  narcotic  action.  This  also  holds  true 
for  the  augmentation  of  physiological  activity  resulting  from  the 
introduction  of  halogen  atoms,  for  chloroform  during  narcosis  is 
excreted  almost  entirely  in  unaltered  form,  being  decomposed  scarcely 
at  all  in  the  body.  The  setting  free  of  chlorine,  therefore,  cannot 
be  the  cause  of  this  so  strikingly  augmented  physiological  activity 
of  chloroform  as  compared  with  its  chlorine-free  mother  substance, 
methane. 

An  instructive  example  of  these  relationships  is  also  presented  by 
the  halogen  substitution  products  of  isovalerylurea.  In  the  cold- 
blooded animals  the  chlorine,  bromine,  and  iodine  substitution  products 
of  this  substance  are  much  more  strongly  narcotic  than  is  the  halogen- 
free  mother  substance.  As,  however,  the  halogen  is  present  in  a  suffi- 
ciently firm  combination  only  in  the  chlorine  and  bromine  substitution 
products,  and  as  the  iodine  substitution  product  is  decomposed  and 
rapidly  loses  its  iodine  at  the  temperature  of  warm-blooded  animals, 
this  last  combination  behaves  quite  differently  in  the  warm-blooded 
animals  than  do  the  other  two,  being  no  more  active  at  this  higher 
body  temperature  than  is  the  halogen-free  mother  substance  (v.  d. 
Eeckhout).  It  is  thus  clear  that  the  halogen  in  the  molecule  augments 
its  activity  only  so  long  as  it  is  able  to  influence  the  properties  of  the 
whole  atom  complex. 

BIBLIOGRAPHY 

Baumann  u.  Kast:  Zeitschr.  f.  physiol.  Chemie,  1899,  vol.  14,  p.  52. 

Diehl:  Inaug.-Diss.,  Marburg,   1894. 

v.  d.  Eeckhout:    Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  57,  p.  338. 

Fischer  u.  v.  Mering:    Therapie  d.  Gegenw.,  1903. 

Fuchs  u.  Schultze :  Miinchn.  med.  Wochenschr.,  1904,  No.  25. 

Hildebrandt:    Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  53,  p.  90. 

Kionka:  Arch,  intern,  de  Pharmacodyn.  et  de  Therap.,  vol.  7,  p.  476. 

v.  Ley:  Inaug.-Diss.,  Strassburg,  1889. 

v.  Mering  u.  Schneegans:  Therap.  Monatsh.,  1892,  p.  327. 

THEORY  OF  NARCOSIS 

A  theory  of  narcosis  formulated  by  Hans  Meyer1  and  Overton, 
which  may  now  be  discussed,  permits  us  to  determine  which  physical 
or  chemical  properties  of  the  narcotics  are  responsible  for  their 
activity  and  to  learn  in  what  fashion  these  properties  are  modified 
by  the  presence  of  certain  radicals  in  the  molecule. 

As  early  as  1876,  Buchheim 1  defined  the  aim  and  task  of  pharma- 
cologists as  consisting,  first,  in  determining  at  which  point  in  the  body 
a  drug  acted,  and,  second,  in  explaining  such  actions  by  a  reaction 
between  the  cell  constituents  and  the  drug.  This  second  problem,  that 
of  showing  how  the  pharmacological  actions  are  due  to  the  properties 
of  the  chemical  substances  which  produce  them  and  to  their  action  on 


THEORY  OF  NARCOSIS  101 

the  cells  affected,  has,  up  to  the  present  time,  been  successfully  solved 
in  a  few  instances  only,  of  which  carbon  dioxide  poisoning  is  one. 
Conditions  similar  to  those  involved  in  the  reaction  between  carbon 
dioxide  and  haemoglobin  may  also  be  assumed  to  explain  the  elective 
action  of  curarine  and  other  ammonium  bases  on  motor  nerve-endings 
(Fiihner).  However,  the  formation  of  a  chemical  combination  be- 
tween the  drug  and  some  constituent  of  the  protoplasm,  which  (after 
the  analogy  with  the  action  of  carbon  dioxide)  we  are  justified  in 
assuming,  may  in  many  instances  be  assumed  only  in  the  case  of 
such  foreign  substances  as  are  chemically  active. 

Among  the  narcotics  of  the  aliphatic  series,  on  the  other  hand, 
there  are  many  chemically  entirely  inactive  substances  which  exert  a 
characteristic  narcotic  action  on  the  nervous  system.  If  we  wish  to  learn 
which  of  their  properties  are  responsible  for  the  pharmacological 
actions  exerted  in  common  by  the  narcotics  of  this  series,  which  in 
their  chemical  behavior  differ  from  each  other  so  decidedly,  we  must 
look  for  those  properties  common  to  all  of  them, — to  those  among  them 
chemically  least  active,  for  example,  the  saturated  hydrocarbons;  as 
well  as  to  those  chemically  most  active,  for  example,  the  aldehydes, 
such  as  choral  hydrate. 

LIPOID  SOLUBILITY. — It  has  been  found  that  all  possess  the  physical 
property  of  being  soluble  in  both  water  and  fats.  This  especial 
solubility  in  fats,  associated  with  a  sufficient  solubility  in  water,  ia 
essential  for  the  absorption  of  the  narcotics  by  the  cells  and  is  respon- 
sible for  their  peculiar  distribution  in  the  different  tissues  of  the  body, 
and  by  the  physical-chemical  theory  of  narcosis  explains  the  pharma- 
cological action  of  the  narcotics. 

As  early  as  1847,  shortly  after  the  discovery  of  ether  and  chloro- 
form anaesthesia,  Bibra  and  Harless  sought  to  explain  their  anaesthetic 
power  as  the  result  of  their  power  of  dissolving  fat.  As  a  result  of 
quantitative  determinations  of  the  fat  contents  of  normal  and  narco- 
tized animals,  they  believed  that  they  had  found  out  that  the  anaes- 
thetics actually  removed  larger  or  smaller  quantities  of  fat-like 
substances  from  the  brain.  They  assumed,  consequently,  that  these 
drugs  were  responsible  for  a  sort  of  extraction  of  fat-like  substances 
from  the  brain,  and  considered  that  this  was  the  cause  of  anaesthesia. 

However,  there  can  be  no  question  of  such  extraction  of  the  fat- 
like  constituents  of  the  nerve-cells,  for  this  would  be  inconsistent  with 
the  characteristic  rapid  restoration  of  function  which  follows  interrup- 
tion of  anesthetization. 

Hermann  investigated  the  haemolytic  action  of  ether,  chloroform,  etc.,  and 
explained  this  by  their  power  of  dissolving  the  lecithin  of  the  red  blood-cells, 
and  drew  a  parallel  between  this  and  the  narcosis  of  the  central  nervous  system 
with  its  large  content  of  lecithin. 

These  two  hypotheses,  therefore,  contained  the  correct  central  idea 
of  explaining  the  narcotic  action  of  various  drugs  by  their  common 


102   PHAR3VIACGLOGY  O,F  CENTRAL  NERVOUS  SYSTEM 

property  of  ready  solubility  in  the  fats,  for  they  produce  their  effects 
on  the  central  nervous  system  because  they  go  into  solution  in  the 
fat-like  constituents,  the  lipoids,  of  nervous  tissues,  and  form  a 
physical-chemical  combination  with  them. 

ELECTIVE  ABSORPTION  BY  THE  NERVOUS  SYSTEM. — Long  ago,  Buch- 
heim  -  stated  clearly  that  the  pharmacological  actions  affecting  chiefly 
the  nervous  system  were  to  be  considered  as  the  result  of  reactions 
with  those  cell  constituents  ' '  which  are  peculiar  to  the  nervous  system 
or  which  occur  chiefly  there. "  As  a  matter  of  fact,  the  central  nervous 
system  differs  from  other  tissues  especially  in  the  large  quantity  of  its 
fat-like  constituents.  A  substance  foreign  to  the  body,  moreover,  can 
produce  a  pharmacological  action  only  where  it  is  absorbed  in  sufficient 
quantities  by  the  cells.  Consequently,  a  necessary  primary  condition 
for  the  elective  action  of  the  narcotics  on  the  nervous  system  is  its 
sufficient  absorption  by  the  functional  elements.  Narcotic  substances 
must  first  of  all  be  neurotropic,  in  the  sense  in  which  this  expression 
was  first  employed  by  Ehrlich. 

Ehrlich1  was  the  first  to  attribute  the  absorption  and  storing  up  of  various 
substances  by  the  nervous  system  to  their  affinity  to  its  lipoid  constituents,  and 
especially  to  emphasize  the  importance  of  studying  the  distribution  in  the  body 
and  in  various  organs  of  pharmacologically  active  substances.  For  such  investi- 
gations he  employed  chiefly  dyes,  the  distribution  of  which  is  so  readily  apparent 
after  intravital  staining  or  so  readily  demonstrable  by  various  reactions.  Start- 
ing with  these  ideas,  he  demonstrated  that  the  majority  of  the  basic  dyestuffs, 
which  are  absorbed  by  the  brain,  are  also  stored  up  in  various  other  fatty  tissues. 
Neurotropism  and  lipotropism  thus  go  hand  in  hand.  If  now  a  sulphonic  acid 
radical  was  introduced  into  a  neurotropic  dyestuff,  its  distribution  in  the  body 
was  found  to  be  entirely  altered,  the  dyestuff  losing  its  neurotropic  properties 
as  a  result  of  the  introduction  of  the  acid  radical ;  and  Ehrlich  drew  the  parallel 
between  this  observation  and  the  fact  that  neurotoxic  substances,  such  as  phenol, 
certain  alkaloids,  etc.,  as  a  rule  lost  their  toxicity  as  a  result  of  the  introduction 
of  the  sulphonic  acid  radical  and  at  the  same  time  lost  their  neurotropic 
character. 

Ehrlich2  was  thus  able  to  demonstrate  for  the  dyestuffs  the  manner  in 
which  their  affinity,  and  thus  their  power  of  penetrating  into  the  nervous  cells, 
was  altered  by  certain  changes  in  their  constitution,  and  to  show  that,  as  a 
result,  their  distribution  in  the  tissues  was  a  factor  having  an  important  bearing 
upon  the  relationship  between  chemical  constitution  and  pharmacological  action. 

The  ready  solubility  of  the  narcotics  in  fatty  substances  conse- 
quently determines  the  manner  in  which  they  are  distributed  in  the 
various  organs  and  cells.  This  solubility  in  fats  is  also  a  prime 
requisite  for  the  absorption  of  foreign  substances  by  all  cells.  Overtoil 
has  proved,  for  the  majority  of  organic  substances,  that  the  greater 
their  solubility  in  fat,  as  compared  with  their  solubility  in  water,  the 
more  rapidly  do  they  penetrate  into  the  protoplasm.  He,  consequently, 
assumed  that  the  protoplasmic  membrane  is  impregnated  with  certain 
substances,  the  lipoids,  which  possess  solution  affinities  similar  to  those 
of  the  fats. 

In  addition  to  a  solubility  in  fat,  a  certain  solubility  in  water  is 
also  essential  if  a  substance  is  to  be  absorbed.  Substances  which  are 


THEORY  OF  NARCOSIS 


103 


entirely  insoluble  in  water  and  which  are  also  not  volatile  are  either 
split  up  in  order  that  they  may  be  absorbed,  as  is  the  case  with  the 
fats,  or,  like  paraffin,  they  are  not  absorbed. 

DISTRIBUTION  OF  NARCOTICS  IN  THE  ORGANISM. — The  distribution 
of  a  substance  throughout  the  body  is,  therefore,  determined  not  only 
by  its  solubility  in  fats,  but  by  its  relative  solubility  in  fat  and  in 
aqueous  media.  That,  as  a  matter  of  fact,  the  narcotics,  when  dis- 
tributed about  in  the  body,  are  absorbed  to  the  greatest  extent  by  those 
cells  and  organs  in  which  fat-like  substances  preponderate,  is  shown 
by  the  following  facts:  Chloroform  is  present  in  larger  quantities  in 
the  red  blood-cells  than  in  the  serum,  because  lecithin  and  cholesterin, 
chloroform-soluble  constituents  of  the  erythrocytes,  absorb  it  in  rela- 
tively larger  quantities  (Pohl).  Ether,  chloral  hydrate,  and  acetone 
are  distributed  in  the  same  unequal  fashion  between  the  blood-cells 
and  the  plasma  (Frantz,  Archangelsky) .  The  distribution  of  these 
various  substances  in  the  different  organs  of  the  body  follows  the  same 
law  of  distribution.  The  accompanying  table  gives  the  results  of 
Nicloux's  investigation  of  the  distribution  of  chloroform. 

Distribution  of  Chloroform  in  Anaesthetized  Dogs  (Nidoux). 


Duration  of  anaesthesia 

30  min. 

30  min. 

84  min. 

80  min. 

Arterial  blood                 .... 

Per  cent. 

Per  cent. 

0.070 

o!6555 
0.085 
0.083 
0.0505 
0.0465 
0.038 
0.041 
0.0215 

Per  cent. 

0.064 

o!6545 
0.0795 
0.0805 
0.0525 
0.046 
0.031 
0.0395 
0.0245 
0.037 
0.068 
0.132 

Per  cent. 

o!649 
0.046 
0.075 

o!6485 
0.039 
0.031 
0.039 

o!265 
0.0685 
0.0875 

Venous  blood  

0.0525 
0.059 

Cerebrum     

Medulla        

Cord  

Liver     

0.047 
0.0465 
0.0335 

Kidney  

Spleen   

Heart            

Muscle  

0.015 
0.049 

Subcutaneous  fat  

Omental  fat 

Perirenal  fat     

From  this  table  it  is  apparent  that  certain  portions  of  the  nervous 
system,  as  well  as  those  deposits  of  fat  which  are  well  supplied  with 
blood,  contain  larger  amounts  of  chloroform  than  do  the  other  organs. 

Fatty  tissues  are  thus  seen  to  compete  especially  with  the  nervous  system 
in  respect  to  the  absorption  of  chloroform,  and,  as  a  matter  of  fact,  Atansfeld  l 
has  recently  shown  that  certain  internally  administered  narcotics  act  more 
powerfully  in  emaciated  than  in  well-nourished  animals,  and  that  their  brains 
contain  almost  twice  as  large  a  portion  of  the  chloral  hydrate  administered  as  do 
those  of  well-nourished  animals,  in  which  the  fatty  tissues  absorb  a  portion  of 
the  narcotic.  Such  combinations  between  these  narcotics  and  this  tissue  (the 


104    PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

fat),  as  also  their  combination  with  other  pharmacologically  less  susceptible 
tissues, — e.g.,  the  liver, — do  not  produce  readily  appreciable  results,  for  the 
narcosis  of  the  liver-cells  or  of  the  red  blood-cells  does  not  at  once  express  itself 
by  any  change  in  function,  and  an  acute  injury  of  these  less  susceptible  cells  will 
evidently  be  produced  only  by  a  concentration  which  would  already  have  caused 
death  by  its  actions  on  the  nervous  system.  [Such  effects  are  probably  produced 
not  infrequently  during  anaesthesia.  The  destruction  of  the  red  cells  almost  cer- 
tainly occurs  in  varying  degrees  under  varying  clinical  conditions,  and  acute 
degeneration  of  the  liver,  which  not  infrequently  has  followed  chloroform  anaes- 
thesia, would  appear  to  be  a  late  expression  of  such  action. — TB.] 

SOLUBILITY  REACTIONS  WITH  THE  LIPOIDS. — Certain  observations  on 
the  absorption  of  dyes  by  vegetable  cells  (Pfeffer)  and  by  colloidal 
substances,  such  as  gelatin  plates  (Hofmeister) ,  furnish  some  data 
which  help  us  in  understanding  or  imagining  the  fashion  in  which 
the  "solution  affinity"  of  the  narcotics  for  the  lipoids  determines  the 
proportions  in  which  they  accumulate  in  the  different  tissue  cells. 
These  dyestuffs  pass  from  dilute  aqueous  solutions  and  accumulate  in 
vegetable  cells  or  gelatin  plates  in  much  greater  concentration,  forming 
firm  physical  combinations  or  solutions  with  the  colloidal  contents  of 
these  cells  or  plates  if  they  possess  a  solution  affinity  for  them, — that 
is  to  say,  if  they  are  more  soluble  in  these  colloids  than  in  water 
(Spiro).  Under  such  conditions  one  may  observe  an  elective  absorp- 
tion, some  dyestuffs  being  rejected  and  the  others  continuing  to  be 
absorbed  until  a  condition  of  equilibrium  has  been  established,  which 
corresponds  to  a  certain  distribution  coefficient  between  the  colloid 
and  water.  If  now  the  colored  vegetable  cells  or  gelatin  plates  are 
transferred  to  water  containing  no  dye,  the  dyestuff  gradually  passes 
back  again  into  the  water.  The  process  is  thus  a  reversible  one.  The 
absorption  of  the  narcotics  by  the  lipoids  of  the  nervous  system  which 
occurs  during  the  narcosis,  and  the  restoration  of  function  after  the 
narcotics  have  been  eliminated  from  the  blood  may  be  considered 
to  take  place  in  a  similar  fashion,  the  whole  process  corresponding 
entirely  with  the  chemical  extraction  by  agitation  of  a  substance  which 
is  soluble  in  different  degrees  in  two  media  which  are  not  miscible  with 
each  other. 

NARCOSIS  THE  RESULT  OP  THIS  "SOLUTION  REACTION." — From  the 
above  discussion,  it  is  apparent  that  the  distribution  of  the  narcotics 
in  the  body  and  their  elective  accumulation  in  the  nervous  system  are 
dependent  on  their  "solution  affinity"  to  the  lipoids.  The  theory 
of  narcosis,  however,  does  not  stop  here,  but  goes  one  step  farther  and 
endeavors  to  explain  the  action  of  the  narcotics  as  due  to  this  solution 
reaction.  According  to  this  theory,  the  absorption  of  the  narcotics 
is  not  merely  a  preliminary  condition  necessary  for  the  occurrence  of 
some  still  unknown  reactions  between  the  narcotics  and  other  con- 
stituents of  the  cells,  but  this  "solution  reaction"  with  the  lipoids  of 
the  nerves  is  the  essential  cause  of  the  narcotic  action.  This  con- 
clusion has  been  reached  as  a  result  of  determining  the  quantitative 


THEORY  OF  NARCOSIS 


105 


relationship  between  the  degree  of  activity  of  the  narcotics  and  their 
distribution  coefficient  between  water  and  fats. 

It  is  naturally  impossible  actually  to  determine  these  distribution 
coefficients  between  the  lipoids  of  the  brain  and  the  blood-plasma 
which,  according  to  the  theory,  will  determine  the  degree  of  the  nar- 
cotic power.  Consequently,  we  must  be  satisfied  with  an  approximate 
expression  of  the  solution  affinity  of  the  narcotics  for  the  lipoids  of 
the  nervous  system  on  the  one  hand  and  the  aqueous  body  fluids  on 
the  other.  The  distribution  coefficient  between  oil  and  water  may 
be  considered  as  such  an  approximate  expression,  and  Hans  Meyer 1 
and  Overton  have  determined  these  coefficients  for  a  very  large  number 
of  otherwise  indifferent  narcotic  substances,  and  have  compared  them 
with  the  narcotic  power  of  the  different  substances,  which  is  expressed 
by  the  smallest  molecular  concentration  sufficient  to  narcotize  small 
tadpoles  or  fishes  swimming  in  the  solutions.  The  threshold  value  for 
the  appearance  of  the  narcosis  may  be  quite  exactly  determined  by  this 
method,  because  a  constant  condition  of  equilibrium  is  established 
between  the  solution  containing  a  certain  amount  of  the  drug  and  the 
animals  swimming  about  in  it.  For  example,  in  a  solution  containing 
one  and  one-half  per  cent,  of  ethyl  alcohol,  tadpoles  are  completely 
narcotized  in  2-3  minutes,  and  a  narcosis  of  constant  degree  is  main- 
tained for  hours.  In  a  1  per  cent,  solution,  on  the  other  hand,  no 
complete  narcosis  results,  even  when  they  remain  therein  for  days. 

The  comparison  of  the  distribution  coefficient  with  the  degree  of 
the  narcotic  action  of  the  different  substances  shows  that  the  molecular 
concentration  sufficient  to  produce  narcosis  diminishes  with  almost 
complete  regularity  as  the  coefficient  of  distribution  increases.  The 
narcotic  power  thus  increases  with  the  relative  solubility  in  fat  as  com- 
pared with  the  solubility  in  water,  as  is  shown  by  the  accompanying 
examples : 


Distribution  coefficient. 
Solubility  in  fat 

Effective  molecular 

Solubility  in  water 

Trional  

4.4 

00013 

Tetronal  

4.0 

00018 

Suphonal  

1.1 

0006 

Bromal  hydrate  

07 

0  002 

Chloral  hydrate  

0.22 

0025 

Ethvlurethane  

0.14 

0025 

Alcohol  

0.03 

05 

A  further  proof  that  the  narcotic  powers  of  these  drugs  stand  in 
a  regular  relationship  to  their  distribution  coefficients  has  been  fur- 
nished by  a  series  of  experiments  in  which  a  comparison  was  made  of 
the  narcotic  power  of  certain  substances  at  different  temperatures, 


106   PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 


certain  drugs  being  used  whose  coefficients  of  distribution  between  oil 
and  water  were  distinctly  altered  by  the  changes  of  temperature  (Hans 
Meyer2). 


Threshold  of  narcotic 
action,  effective  dilution 
of  the  normal  solutions 

Partition  coefficient 
Solubility  in  fat 

Solubility  in  water 

At  3°  C. 

At  30°  C. 

At  3°  C. 

At  30°  C. 

Salicylamide  

1      1300 

1    500 
1     90 

1     3 
1     50 
1     3 

1    600 
1    200 
1    70 

1    7 
1     250 
1    7 

2.23 

0.67 
0.093 

0.024 
0.053 
0.140 

1.40 
0.43 
0.066 

0.046 
0.236 
0.195 

Benzamide     

Monacetin  

Ethyl  alcohol  

Chloral  hydrate       .... 

Acetone  

With  three  of  these  substances  the  distribution  coefficient  is  in- 
creased by  heating  from  3°  to  30°,  while  with  three  others  the  opposite 
effect  is  produced.  Entirely  in  accordance  with  this  increase  or 
diminution  in  the  relative  solubility  in  fat,  the  narcotic  power  of  the 
substances  rises  or  falls,  so  that,  for  example,  tadpoles  at  30°  C.  are 
just  narcotized  by  a  certain  concentration  of  chloral  hydrate,  but  wake 
up  again  when  the  solution  is  cooled  and  are  again  narcotized  when 
the  solution  is  again  warmed. 

By  these  investigations  proof  has  been  furnished  for  the  causal 
relationship  between  the  narcotic  action  of  certain  indifferent  lipoid- 
soluble  substances  and  the  power  of  the  nervous  system  to  attract  and 
retain  them.  However,  there  are  still  differences  of  opinion  as  to  the 
significance  of  these  relationships.  There  are  those  who  have  been 
willing  to  see  in  the  cell  lipoids  of  the  nervous  system  only  the  solvent 
which  brings  the  narcotics  into  contact  with  the  functioning  nucleus 
of  the  susceptible  cells,  where  they  are  able  to  react  with  other 
constituents  of  the  cells  which  are  still  entirely  unknown  to  us. 
According  to  this  conception,  assumed  that  this  attraction  and 
retention  are  essential  preliminary  conditions  for  the  pharmaco- 
logical action,  and  that,  for  example,  increasing  temperature,  by  alter- 
ing the  solution  affinity,  will  be  accompanied  by  a  similar  change  in 
the  degree  of  the  pharmacological  action.  However,  the  very  extensive 
quantitative  parallelism  between  the  pharmacological  power  of  the 
different  narcotics  and  their  coefficients  of  distribution  is  not  suffi- 
ciently explained  by  this  assumption,  for  if  the  contact  action,  which 
cannot  be  followed  further,  is  assumed  to  take  place  between  the 
narcotics  which  have  penetrated  into  the  interior  of  the  cells  and  an 
unknown  substance  or  mixture  of  substances,  one  would  be  forced 
to  conclude  that  the  strength  of  this  contact  action  is  necessarily 
quantitatively  alike  with  the  different  narcotics,  otherwise  the  paral- 


THEORY  OF  NARCOSIS  107 

lelism  between  the  narcotic  power  and  the  concentration  in  the  cell 
lipoids  could  not  be  maintained.  If  one,  however,  assumes  that  the 
narcotics  and  some  unknown  constituents  of  the  nerve-cells — for 
example,  the  proteids — enter  into  a  physical-chemical  reaction,  on 
the  degree  of  which  the  narcotic  activity  must  depend,  this  hypothe- 
tical reaction  would  necessarily  follow  the  same  scale  of  chemical 
relationship  as  do  their  soluble  affinities  to  fats.  In  other  words,  these 
hypothetical  cell  constituents  must  also  possess  lipoid  properties; 
otherwise  the  narcotic  power  could  not  remain  parallel  with  the  dis- 
tribution coefficients  of  solubility  in  fats.  Consequently,  we  see  in  the 
lipoids  of  the  nerve-cells  not  merely  substances  which  act  as  the  means 
of  bringing  about  a  solution  of  the  narcotics  in  the  cells,  but  we  see 
in  them  the  actual  substance  or  substances  which  are  acted  upon  by  the 
narcotics.  As  a  result  of  their  loose  physical-chemical  combination 
with  the  narcotics,  these  lipoids  lose  their  normal  relationship  to  the 
other  cell  constituents,  and  as  a  result  the  entire  chemism  of  the  cell 
is  inhibited. 

Among  the  results  of  this  inhibition  is  a  diminished  absorption  or  utiliza- 
tion of  oxygen,  which  has  been  shown  by  Verworn  and  his  collaborators  to  occur 
in  narcosis.  This  deprivation  of  oxygen  by  itself  produces  a  depressing  or 
paralytic  effect  very  much  in  the  same  way  as  does  narcosis  (Mansfeld*,3).  The 
inhibition  of  oxidation  is,  therefore,  certainly  a  factor  accompanying  chloroform 
or  ether  anaesthesia  which  tends  to  augment  the  narcosis,  but,  just  as  certainly, 
it  is  not  the  cause  of  the  anaesthesia,  for  vital  phenomena,  such  as  nervous 
excitation,  are  inhibited  only  by  many  times  greater  degrees  of  narcosis  than  are 
necessary  to  cause  an  inhibition  of  the  consumption  of  oxygen  (Dontas,  Hober, 
Warburg1,2),  and,  furthermore,  narcosis  inhibits  those  very  phenomena  of  life 
for  which  energy  is  not  furnished  by  oxygen  (Winterstein) . 

There  has  been  a  wide-spread  tendency  to  assume  that  the  pro- 
teids alone  are  essential  factors  in  the  functional  activity  of  cells, 
but  the  general  occurrence  of  lecithine  and  other  lipoids  in  all  living 
cells  speaks  against  this  view.  It  appears  that  these  substances  do 
not  play  in  the  cell  a  role  of  reserve  substances  as  do  the  true  fats,  but 
that  they  are  combined  intimately  with  proteid  to  form  a  portion  of  the 
functioning  protoplasm.  Combinations  of  lecithin  and  proteid,  how- 
ever, manifest  similar  solution  affinities  to  those  of  lecithin  and  must, 
therefore,  in  their  relationship  to  this  narcosis  theory,  be  considered 
as  lipoids. 

The  fact  that  the  narcotics  of  this  series  possess  the  power  of 
paralyzing  not  only  nervous  elements  but  also  all  living  cells  is  quite 
in  accord  with  this  general  distribution  of  the  lipoids  in  all  cells. 
That  the  narcotics  are  primarily  neurotoxic  is  due  to  the  fact  that  the 
disturbance  of  function  which  they  cause  expresses  itself  most  clearly 
in  the  nervous  organs. 

SIDE  ACTIONS  OP  THESE  DRUGS. — This  theory  of  narcosis  is  based 
on  the  presumption  that  further  investigations  will  confirm  this  paral- 
lelism between  the  anaesthetic  power  and  the  partition  coefficient  of 


108   PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

solubility  in  the  lipoids  and  the  plasma.  In  no  case,  however,  is  an 
absolute  parallelism  to  be  expected,  for  the  partition  coefficient  be- 
tween oil  and  water  is  only  an  approximate  expression  for  the  actual 
distribution  of  the  ancesthetics  between  the  cerebral  lipoids  and  the 
blood-plasma.  Above  all,  it  is  only  with  those  members  of  this  group 
which  are  chemically  indifferent  and  which  do  not  readily  enter  into 
chemical  reactions  that  one  may  assume  an  absence  of  affinities  for 
other  constituents  of  the  nervous  tissues.  As  a  matter  of  fact,  the 
various  side  actions  of  the  different  narcotics  indicate  clearly  that 
such  side  reactions  also  occur.  However  this  may  be,  the  basic  narcotic 
action  of  the  different  members  of  the  alcohol-chloroform  group  is, 
in  principle,  so  similar,  that  we  are  compelled  to  assume  that  it  is 
caused  by  a  reaction  which  is  common  to  them  all.  The  more,  however, 
the  essential  pharmacological  actions  of  narcotic  substances  differ  from 
the  typical  action  of  this  group,  the  more  necessary  is  it  to  assume  that 
other  reactions  are  involved  in  producing  their  atypical  actions.  Thus, 
for  example,  phenol,  as  a  lipoid  soluble  substance,  might  be  considered 
as  belonging  to  this  group,  and,  as  a  matter  of  fact,  it  does  produce 
some  narcotic  effects,  but,  as  it  possesses  strong  affinities  for  proteids 
and  other  constituents  of  the  body,  it  also  produces  its  own  peculiar 
pharmacological  effects. 

OTHER  TYPES  OF  ANAESTHESIA. — This  theory  cannot  by  any  means 
be  used  to  explain  every  kind  of  anaesthesia,  for  many  other  quite 
different  disturbances  of  the  chemical  equilibrium  of  the  nerve-cells 
must  inhibit  their  functions  and  produce  superficially  similar  symp- 
toms, as  is,  for  example,  the  case  with  the  salts  of  magnesia 
(Meltzer1,2).  The  method  of  action  described  above  applies,  there- 
fore, only  to  chemically  relatively  indifferent  substances. 

In  this  sense,  substances  such  as  free  C02  and  N02  which  chemically 
do  not  even  remotely  resemble  the  members  of  the  aliphatic  series,  may 
also  be  considered  as  belonging  pharmacologically  to  the  group  of 
alcohol,  for  they  act  as  narcotics  and  are  soluble  in  the  lipoids,  while 
the  carbonates,  which  do  not  produce  such  effects,  are  also  insoluble 
in  the  lipoids.  On  the  other  hand,  it  is  in  the  highest  degree  probable 
that  besides  being  soluble  in  the  lipoids  the  alkaloids  possess  other 
affinities  for  other  cellular  constituents,  for  the  manifold  character 
of  their  pharmacological  actions  of  itself  indicates  that  they  must  act 
on  different  constituents  of  the  nerve-cells.  The  alkaloidal  drugs  do 
not  exhibit  such  a  uniform  type  of  pharmacological  action  as  do  the 
members  of  the  alcohol  group,  as  is  shown  by  the  fact  that  not  all  types 
of  cells  are  pharmacologically  influenced  by  them,  numerous  vegetable 
cells,  for  example,  being  entirely  unaffected,  a  fact  which  by  itself 
renders  it  improbable  that  their  fundamental  action  is  due  to  their 
affinity  to  the  lipoid  substances,  which  are  such  universal  constituents 
of  cells. 


CENTRAL  DEPRESSANTS  109 

BIBLIOGRAPHY 

Archangelsky :    Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46. 

Bibra  u.  Harless:   Ueber  die  Wirkung  d.  Schwefelathers. 

^uchheim:   Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5,  p.  272. 

2Buchheim:    Arch.  f.  Heilkunde,  1870,  vol.  11. 

Dontas :  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  59,  p.  430. 

'Ehrlich:  Therap.  Monatsh.,  March,  1887. 

2Ehrlich:   Festschr.  f.  Leyden,  1898. 

Frantz:  Inaug.-Diss.,  Wiirzburg,  1895. 

Fuhner:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vola.  58  and  59. 

Hermann:    Arch.  f.  Anat.  u.  Physiol.,  1866. 

Hober:  Z.  f.  allgem.  Physiol.,  1910,  vol.  10,  p.  173. 

Hofmeister:    Arch.  f.  exp.  Path.  u.  Therap.,  1811,  vol.  29. 

1Mansfeld:   Arch.  int.  de  Pharmacodynamie  et  de  Ther.,   1905,  vol.   15;    1907. 

vol.  17. 

"Mansfeld:   Pfliiger's  Arch.,  1910,  vol.  131,  p.  457. 
'Mansfeld:  Pfliiger's  Arch.,  1909,  vol.  129,  p.  69. 
Meltzer,  J.,  u.  J.  Auer:  Am.  Journ.  of  Phys.,  1905-06,  vols.  14,  15,  16;  Journal 

of  Exp.  Med.,  1906,  vol.  8. 
1  Meyer,  Hans:    Zur  Theorie  d.  Alkoholnarkose,  Arch.  f.  exp.  Path.  u.  Pharm., 

1899,  vol.  42. 

2 Meyer,  Hans:    Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46. 
Nicloux:   Les  Anesthesiques  generaux,  Paris,  1908. 
Overton:  Studien  iiber  die  Narkose,  Jena,   1901. 
Pfeffer:  Untersuchung  a.  d.  botan.  Inst.,,  Tubingen,  1866. 
Pohl:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28. 
Spiro:  Habilitationsschrift,  Strassburg,  1897. 
Verworn:  Deut.  med.  Woch.,  1909,  No.  37. 

1  Warburg:  Mtinchn.  med.  Woch.,  1911,  No.  6. 

2  Warburg:   Z.  f.  physiol.  Chem.,  1910,  vol.  69,  p.  452. 
Winterstein:  Z.  f.  allgem.  Physiol.,  1907,  vol.  6,  p.  315. 

OTHER  CENTRAL  DEPRESSANTS 

In  this  chapter  mention  has  been  made  only  of  the  therapeutically 
most  important  of  the  many  organic  drugs  which  exert  pharmacological 
actions  on  the  central  nervous  system.  Such  actions  of  numerous 
other  drugs  will  be  described  in  connection  with  the  discussion  of 
their  other  more  important  actions  on  other  organs.  Other  drugs, 
again,  which  act  primarily  and  chiefly  on  the  central  nervous  system 
possess  only  a  toxicological  significance,  although  among  them  are  some 
which  formerly  were  widely  used  in  medicine,  but  which  are  to-day 
used  so  seldom  that  they  may  be  dismissed  with  a  few  words. 

ACONITE,  the  root  of  Aconitum  napellus,  or  monkshood,  is  such  a 
drug,  which  is  official  and  is  still  quite  extensively  used,  particularly 
by  the  homoeopaths.* 

The  various  aconitines  on  the  market  differ  quite  markedly  from  one 
another,  but  are  all  esters  of  various  aconines  with  acetic,  benzoic,  and  other 
acids.  Locally  applied,  they  cause  a  primary  stimulation  followed  by  a  later 
depression  of  the  sensory  nerve-endings,  causing  first  a  feeling  of  warmth  and 
tingling  and  later  anaesthesia.  Repeated  administration  of  doses  of  1-2  mg. 
causes  parsesthesia,  formication,  and  numbness  of  the  extremities,  with  diminution 
or  complete  abolition  of  sensations  of  pain,  such  as  those  of  neuralgia.  These 


110  PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

systemic  effects  are  probably  the  result  of  their  action  on  the  central  nervous 
system  or  on  the  spinal  ganglia  (Wartmann,  Cohn).  Toxic  doses  are  followed  by 
convulsions,  due  to  asphyxia,  and  by  paralysis  and  death.  Even  very  small  doses, 
mere  fractions  of  a  milligram,  may  cause  serious  symptoms,  and  3-4  mg.  of 
aconitine  nitrate  may  cause  death.  The  cases  of  poisoning  which  have  been 
reported  have  usually  been  due  to  the  variable  strength  of  the  different  aconitine 
preparations  (Kunkel,  Kornalewski). 

BIBLIOGRAPHY 

Cohn:   Diss.,  Berlin,  1888. 

Kornalewski:   Ztschr.  f.  Medizinalbeamte,   1904,  p.  469. 

Kunkel:   Handb.  d.  Toxikol.,  1901,  p.  67. 

Wartmann:  Diss.,  Wtirzburg,  1883. 

Numerous  inorganic  substances  also  exert  toxic  actions  on  the 
central  nervous  system,  and  even  those  salts  which  are  normal  con- 
stituents of  the  body  may  produce  these  effects  if,  as  a  result  of  their 
intravenous  or  subcutaneous  administration  in  too  large  quantities, 
the  normal  equilibrium  of  the  different  ions  is  disturbed. 

MAGNESIUM  SALTS  occupy  a  peculiar  position  among  the  salts, 
causing,  without  any  primary  stimulation,  an  elective  paralysis  of  the 
central  nervous  system,  the  heart  being  hardly  at  all  affected  by 
them  and  the  muscles  retaining  their  excitability  (Meltzer  and  Auer*). 
It  appears  that  Mg  ions,  which  in  relatively  small  amounts  are  normal 
constituents  of  the  tissues,  when  .present  in  sufficient  concentrations 
abolish  the  excitability  of  all  nervous  organs.  In  the  frog  a  curare- 
like  paralysis  of  the  motor  nerve-endings  is  the  most  striking  effect 
produced  (Binet).  This  effect  is  produced  also  in  warm-blooded 
animals,  but,  as  it  occurs  later  than  does  the  stoppage  of  the  respira- 
tion, it  can  be  observed  only  if  artificial  respiration  be  carried  on 
( Wiki) .  This  effect  on  the  respiration  is  preceded  by  complete  anaes- 
thesia, paralysis  of  the  higher  motor  centres,  and  depression  of  the 
blood-pressure  (Meltzer  and  Auer 2) .  The  vagus  nerve-endings  also  lose 
their  excitability,  and  the  motor  and  sensory  nerve-trunks,  if  brought 
in  direct  contact  with  magnesium  salts,  lose  their  conductivity.  Quite 
recently  these  actions  have  been  utilized  in  practice  (Meltzer}  [but, 
with  the  exception  of  the  local  anaesthetic  actions,  apparently  with  little 
success.  Injected  intradurally,  solutions  of  magnesium  salts  cause  a 
spinal  analgesia  resembling  that  produced  by  cocaine,  but  more  lasting. 
Practical  experience  with  this  method  has,  however,  shown  that  it  is 
attended  by  such  danger  that  it  has  been  abandoned,  at  any  rate  for 
the  present. — TR.]. 

All  the  toxic  symptoms  produced  by  magnesium  salts  may  be 
caused  to  disappear  promptly  by  the  intravenous  injection  of  calcium 
salts  (Meltzer  and  Auer*),  calcium  ions  appearing  to  act  antago- 
nistically to  those  of  magnesium  and  to  be  able  to  restore  the  equi- 
librium between  the  various  ions  when  it  has  been  disturbed  by  an 
excess  of  Mg  ions. 


THE  BROMIDES  111 

BIBLIOGRAPHY 

Binet:  Revue  medic  de  la  Suisse  romane,  1892,  p.  523. 

Meltzer:   Berl.  klin.  Woch.,  1906,  No.  3. 

i  Meltzer,  S.  J.,  u.  J.  Auer:  Am.  Journ.  of  Physiol.,  1905-06,  vols.  14,  15,  and  16. 

a  Meltzer,  S.  J.,  u.  J.  Auer:  Journ.  of  Exp.  Med.,  1906,  vol.  8. 

'Meltzer,  J.,  u.  J.  Auer.,  Am.  Journ.  of  Physiol.,  1908,  vol.  21,  p.  400. 

Wiki :  Journal  de  physiologic  et  pathol.  generate,  1906,  No.  5. 

POTASSIUM  SALTS  do  not  cause  such  a  well-developed  elective 
paralysis,  but  when  administered  intravenously  or  subcutaneously 
they  exert  toxic  actions  both  on  the  nervous  system  and  on  the  heart. 
[It  is  in  the  highest  degree  improbable  that  the  medicinal  adminis- 
tration of  potassium  salts  ever  produces  such  a  "potassium"  toxic 
action.  The  common  belief  that  potassium  salts  are  "too  depressing" 
is  based  only  on  a  misinterpretation  of  experimental  evidence. — TB.] 

THE  BROMIDES 

The  anions  of  neutral  salts,  particularly  Br  ions,  may  also  exert 
specific  therapeutically  useful  actions  on  the  nervous  system.  As  these 
salts  in  their  pharmacological  actions  show  a  certain  resemblance  to 
the  hypnotics,  it  is  appropriate  to  take  up  their  discussion  at  this  time. 
In  the  body  the  bromides  of  the  different  alkaloids  produce  entirely 
similar  pharmacological  effects,  and  consequently  their  pharmacological 
actions  must  be  attributed  to  their  bromine  component  and  not  to 
their  different  metallic  components  (K,  Na,  etc.). 

Soon  after  Ballard  in  1826  discovered  bromine  and  the  bromides,  KBr 
was  employed  in  therapeutics,  at  first  as  a  substitute  for  KI,  which  chemically  so 
closely  resembles  it.  Very  soon  its  uselessness  in  lues  was  recognized,  but 
at  the  same  time  its  efficiency  as  a  sedative  for  the  central  nervous  system  became 
apparent.  In  1864  it  was  first  used  by  Behrend  in  certain  forms  of  sleepless- 
ness, and  a  little  later  by  Vigouroux  and  Voisin  in  epilepsy. 

ACTION  OP  LARGE  DOSES  IN  HEALTH. — Concentrated  solutions  of  the 
bromides  irritate  the  tissues  chiefly  as  a  result  of  their  salt  action, 
but  dilute  solutions  produce  no  marked  irritation  and  are  rapidly 
absorbed.  In  man  very  large  doses  (10  gm.),  in  addition  to  causing 
a  salty  after-taste  in  the  mouth  and  a  feeling  of  pressure  and  warmth 
in  the  epigastrium,  cause  a  certain  amount  of  stupor,  with  disturbance 
of  the  powers  of  perception  as  well  as  of  the  speech.  Besides  this,  such 
doses  cause  a  very  complete  abolition  of  the  reflex  irritability  of  the 
palate  and  posterior  pharyngeal  wall,  so  that  gagging  does  not  follow 
mechanical  irritation  (Kross).  The  bromides  are  not  to  be  considered 
true  hypnotics,  for  in  man  therapeutic  doses  of  1-2  gm.  do  not  produce 
a  condition  resembling  normal  sleepiness  and  fatigue.  It  is  in  accord 
with  this  that  in  experiments  on  animals  no  narcosis  results  from  the 
administration  of  the  bromides,  but  only  a  diminution  of  the  central 
reflex  excitability  when  large  doses  are  given.  However,  in  states  of 
nervous  excitement  and  in  epilepsy  their  administration  produces  a 
quietiner  or  sedative  effect. 


112  PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

Thus  far  we  have  no  knowledge  of  the  details  of  the  manner  in 
which  these  effects  are  produced.  Psycho-physical  analysis  has  shown 
only  that  the  bromide  salts  influence  those  psychic  processes  which  may 
be  experimentally  measured,  in  a  very  different  fashion  from  the  true 
hypnotics,  for  doses  of  2-4  gm.  neither  impair  the  perception  of 
sensory  stimuli  nor  the  inauguration  of  motor  acts  (Lowald) .  On  the 
contrary,  intellectual  work  is  favorably  influenced  by  the  bromides, 
particularly  if  the  performance  of  such  work  has  been  rendered  diffi- 
cult as  the  result  of  pronounced  feelings  of  discomfort.  It,  therefore, 
appears  that  under  such  circumstances  bromides  eliminate  certain  cen- 
tral excitations,  which  accompany  feelings  of  discomfort  and  which 
interfere  with  the  performance  of  mental  work. 

IN  CONDITIONS  OF  DISEASE  also,  the  bromides  act  favorably  upon 
such  conditions  of  nervous  hyperexeitability  as  are  accompanied  by 
discomfort  or  malaise,  as  is  often  the  case  in  neurasthenia  and  epilepsy. 
Bromides  also  often  produce  sedative  and  hypnotic  effects  in  conditions 
of  hyperexeitability  in  arteriosclerotic  patients  (Hamburger) ,  but,  on 
the  other  hand,  they  are  ineffectual  in  such  conditions  as  simple  mani- 
acal excitement  (Lowald).  It,  therefore,  appears  that,  when  potas- 
sium bromide  is  administered  in  the  usual  hypnotic  and  sedative  doses 
of  1-2  gm.,  its  effects  are  due  to  a  very  specific  action  on  the  cerebral 
cortex. 

ACTION  IN  EPILEPSY. — The  diminution  of  the  reflex  excitability  of 
the  central  nervous  system,  which  may  be  demonstrated  experimentally 
after  large  doses  of  bromides,  appears  to  be  of  significance  in  con- 
nection with  the  use  of  KBr  in  the  treatment  of  epilepsy,  in  which  it 
is  administered  in  daily  dosage  of  5-10  gm.  or  more,  amounts  which 
even  in  normal  individuals  exert  a  distinct  influence  on  the  cerebral 
sensory  and  motor  functions. 

In  experiments  on  animals,  Albertoni  has  shown  that  large  but  non- 
toxic  doses  of  KBr,  especially  when  administered  repeatedly,  markedly 
lessen  the  electric  excitability  of  the  cerebral  motor  centres.  While 
in  the  normal  controls  stimulation  of  the  cortex  with  electric  currents 
of  a  certain  strength  always  caused  general  epileptiform  convulsions, 
showing  that  the  stimuli  spread  from  the  directly  stimulated  centres 
over  the  whole  motor  region,  in  the  bromidized  animals  no  generalized 
convulsions  occurred,  but  only  cloriic  movements  of  the  muscles  whose 
motor  centres  lie  close  to  the  stimulated  points.  This  is  best  explained 
on  the  assumption  that  the  drug  Hocks  or  renders  difficult  the  passage 
of  impulses  along  the  paths  which  connect  the  various  motor  centres. 
While  there  can  be  no  question  of  the  favorable  influence  exerted  by 
the  bromides  on  the  number  and  intensity  of  the  epileptic  attacks, 
we  cannot  obtain  any  closer  insight  into  the  manner  in  which  they  do 
so  until  the  cause  of  epilepsy  is  more  completely  understood. 

RETENTION  IN  THE  BODY. — The  favorable  therapeutic  effects  of  the 
bromides  do  not  become  manifest  until  a  rather  high  degree  of  satura- 


THE  BROMIDES  113 

tion  of  the  organism  has  been  produced,  and  when  this  occurs  the  effect 
in  diminishing  the  epileptic  attacks  persists  for  some  time  after  cessa- 
tion of  medication.  This  is  due  to  the  fact  that  bromides  are  not 
completely  eliminated  in  the  24-36  hours  following  their  ingestion, 
but  that,  in  spite  of  the  fact  that  their  elimination  starts  almost 
immediately,  only  from  one-tenth  to  one-fourth  of  the  amount  adminis- 
tered is  excreted  in  the  first  24—36  hours,  and  that  even  20  days  after 
cessation  of  its  administration  it  has  not  been  completely  eliminated 
(Fere,  Hebert  et  Peyrot,  Nencki,  Pflaumer).  It  is  thus  evident  that 
the  organism  retains  large  amounts  of  bromides  for  a  considerable 
period  (v.  Wyss,12  E.  Frey). 

As  a  result  of  this  retention  when  bromides  are  regularly  ingested, 
a  certain  SATURATION  OF  THE  ORGANISM  results.  While  at  the  start 
from  10  to  48  per  cent,  of  the  daily  dose  is  eliminated,  the  amount 
varying  with  the  amount  of  urine  excreted,  the  percentage  eliminated 
increases  from  day  to  day,  so  that  when,  for  example,  7  to  8  gm.  of 
NaBr  are  taken  daily  for  two  weeks  or  so,  a  state  of  bromine  equilib- 
rium results,  in  which  the  elimination  and  absorption  of  bromine  are 
equal  (Laudenheimer,  v.  Wyss,1*2  Fessel). 

When  bromides  are  taken  regularly,  the  blood  always  contains 
bromides,  and  the  chlorides  are  correspondingly  diminished,  so  that 
when  saturation  has  been  produced  ^4  to  y3  of  the  Cl  of  the  blood- 
serum  has  been  replaced  by  Br  (Laudenheimer,  v.  Wyss,1?  Ellinger). 
The  bromides  also  partially  replace  the  chlorides  in  other  tissues, 
accumulating  in  the  largest  amount  in  those  organs  which  normally 
are  richest  in  chlorine,  in  which  they  to  a  certain  extent  assume  the 
role  of  chlorides.  For  instance,  HBr  appears  in  the  gastric  juice 
(Kiilz,  Nencki}.  According  to  Hoppe,  the  percentage  of  HBr  in  the 
gastric  juice  may  serve  to  indicate  the  degree  of  bromine  saturation 
which  has  been  attained. 

If  this  replacement  of  chlorides  by  bromides  occurs  to  too  great 
a  degree,  toxic  symptoms  appear,  in  which  case  the  free  administra- 
tion of  common  salt  is  curative  (v.  Wyss1'2),  as  it  accelerates  the 
elimination  of  the  bromides  and  replaces  the  bromides  in  the  tissues 
and  body  fluids  (Laudenheimer,  Ellinger} . 

It  is  of  practical  importance  to  remember  that  the  accumulation  of 
bromide  in  the  body  is  influenced  by  the  amount  of  NaCl  ingested,  for 
the  curative  effects  in  epilepsy  are  obtained  more  rapidly  and  with 
smaller  doses  if  the  diet  be  one  poor  in  salt  (Richet).  Bromism,  too, 
occurs  more  rapidly  with  such  diet. 

The  following  figures,  from  Ellinger  and  Kotake,  show  how  in  rabbits  the 
elimination  of  bromides  is  augmented  by  the  simultaneous  administration  of 
NaCl  and  not  by  that  of  the  other  salts,  and  also  show  how  the  blood  contains 
larger  amounts  of  bromides  when  the  diet  is  poor  in  NaCl  than  when  this  salt  is 
administered  freely. 
8 


114  PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

NaBr-NaCl  Experiment.  NaBr-Na  Acetate  Experiment. 

Constant  diet — 0.322  gm.  NaBr  and  Same  diet  and  0.322  gm.  NaBr  and 
2.0  gm.  NaCl  daily  for  6  days  2.0  gm.  sodium  acetate  for  6  days 

Total  Br  excreted 
0.74  gm.  0.41  gm. 

Blood  on  Gth  day  contains 

0.064  per  cent.  Br  =  9.52  per  cent.  0.16  per  cent.  Br—  23.8  per  cent, 

of  the  total  halogen  mols. 

A  comparison  of  the  following  two  experiments  shows  very  strikingly 
how  the  bromine  saturation  when  once  attained  is  rapidly  lessened  by  the 
administration  of  NaCl  and  how  this  salt,  in  contrast  to  other  salts,  accelerates 
the  elimination  of  Br  in  the  urine. 

Period  I. 
Rabbit  A:  Rabbit  B: 

For  8  days  0.322  gm.  NaBr  daily  and  For  8  days  0.322  gm.  NaBr  daily  and 
no  NaCl.  no  sodium  acetate. 

Urine  on  7th  and  8th  days  contains 

Cl  0.67  gm.;  Br  0.28  gm.=  15.3  per  Cl  0.56  gm.;  Br  0.26  gm.  =  16.8  per 
cent,  of  the  total  halogen  mols.  cent,  of  the  total  halogen  mols. 

Blood  on  the  8th  day  contains 

Cl  0.22  per  cent.;  Br  0.15  per  cent.  =  Cl  0.23  per  cent.;  Br  0.16  per  cent.  = 
23.8  per  cent,  of  the  total  halogen  23.8  per  cent,  of  the  total  halogen 

mols.  mols. 

Period  II. 

For  four  days  0.322  gm.  NaBr  +  2.0  For  four  days  0.322  gm.  NaBr  + 
gm.  NaCl  daily  2.0  gm.  sodium  acetate  daily 

Urine  on  1st  and  2d  days  contains 

Cl  2.52  gm.;  Br  0.51  gm.  =  7.7 per  Cl.  0.67  gm.;  Br  0.26  gm.  =  15.3  per 
cent,  of  the  total  halogen  mols.  cent,  of  the  total  halogen  mols. 

Blood  on  the  4th  day  contains 

Cl  0.28  per  cent.;  Br  0.064  per  cent.  Cl  0.24  per  cent;  Br  0.18  per  cent.= 
=  9.2  per  cent,  of  the  total  halogen  23.9  per  cent,  of  the  total  halogen 
mols.  mols. 

BROMISM. — The  accumulation  in  the  body  of  excessive  amounts  of 
bromides  would  appear  to  explain  the  undesirable  bromide  actions 
which  at  times  are  observed.  In  milder  cases  these  affect  chiefly  the 
skin  and  mucous  membranes,  causing  various  exanthematous  eruptions, 
usually  an  acne,  but  in  severer  cases  causing  pustular  eruptions. 
Coryza,  conjunctivitis,  and  eatarrhal  inflammations  of  the  respiratory 
tract  also  occur.  These  lesions  are  probably  all  due  to  irritation  caused 
by  the  bromides  or  their  transformation  products  during  their  excre- 
tion by  the  glands  of  the  skin  and  mucous  membranes,  where,  probably 
under  the  influence  of  acid  secretions,  hydrobromie  acid  is  formed, 
which  is  readily  decomposed,  liberating  free  bromine.  As  bromine  is  a 
powerful  irritant  to  the  tissues,  it  is  easy  to  understand  how  the 
local  lesions  are  produced.  It  is  probable  that  the  gastro-intestinal 
disturbances,  which  are  often  observed  in  cases  of  chronic  bromism  and 


THE  BROMIDES  115 

which  cause  emaciation  and  cachexia,  are  dependent  on  the  excretion 
of  the  bromides  through  the  alimentary  mucosa.  Disturbances  of  the 
central  nervous  system,  leading  to  loss  of  memory  and  apathy  and  to 
motor  and  sensory  disturbances,  may  also  be  observed.  NaCl  may  be 
used  as  an  antidote  in  such  conditions.* 

PREPARATIONS. — For  therapeutic  purposes  the  bromides  of  the  alkalies  are 
the  preparations  most  used.  Those  most  commonly  used  are  potassium  bromide 
(67  per  cent.  Br),  sodium  bromide  (77  per  cent.  Br),  and  ammonium  bromide 
(81  per  cent.  Br),  which  are  all  colorless  crystalline  powders  very  soluble  in 
water,  and  with  a  salty,  rather  disagreeable  taste.  With  the  two  first  named 
no  qualitative  or  quantitive  differences  are  observed  in  their  pharmacological 
action,  except  that  the  sodium  salt  is  slightly  more  powerful  on  account  of  its 
larger  bromine  content.  With  large  doses  of  ammonium  bromide  the  local  and 
systemic  actions  of  its  basic  component  are  evident.  In  order  to  avoid  gastric 
irritation,  these  salts  should  be  administered  well  diluted  with  water. 

With  the  idea  of  avoiding  the  undesirable  effects  of  the  bromides  a  num- 
ber of  organic  bromine  compounds  have  recently  been  introduced,  for  which 
various  advantages  have  been  claimed.  In  judging  of  these  claims  it  must  not  be 
forgotten  that  these  organic  compounds  contain  much  smaller  quantities  of 
bromine  than  the  inorganic  bromides,  which  probably  explains  their  slighter 
toxic  power  [and  also  their  slighter  therapeutic  efficiency. — TR.]  Among  these 
may  be  mentioned :  Bromipin,  brominized  sesame  oil,  obtainable  in  two  strengths, 
10  per  cent,  and  33y3  per  cent.  Br;  sabromin,  dibrombehenate  of  calcium,  contain- 
ing 29  per  cent.  Br;  and  bromine  compounds  with  albumin,  such  as  bromeigone 
(11  per  cent.  Br),  or  with  gelatin,  such  as  bromocoll  (about  20  per  cent.  Br). 
Up  to  the  present  neither  clinical  experience  nor  experimental  evidence  has 
demonstrated  that  these  preparations  possess  any  real  superiority  to  the  bromide 
salts  ( Bilinski,  Hermann ) . 

Valerian  is  another  drug  producing  mild  hypnotic  effects,  which,  although 
no  longer  so  highly  esteemed  as  formerly,  is  still  often  used  in  hysterical  patients. 
As  the  active  constituents  of  the  drug  are  very  unstable,  its  galenic  preparations 
are  of  uncertain  and  variable  potency. 

The  active  constituents  which  are  present  in  the  oil  of  valerian  exert  some 
narcotic  action  on  the  cord  and  the  higher  cerebral  centres  (Binz,  Grisar).  From 
it  there  have  been  isolated  borneol  and  the  bornyl  esters  of  different  fatty  acids, 
particularly  isovalerianic  acid,  which  esters,  like  the  crude  drug,  exert  a  distinct 
depressing  action  on  the  central  nervous  system  (Kionka).  Borneol  isovalerate 
under  the  name  of  bornyval,  and  a  mixture  of  menthol  with  the  menthyl  ester 
of  valerianic  acid  under  the  name  of  validol,  have  been  introduced  as  substitutes 
for  the  crude  drug  or  its  galenic  preparations,  but  they  too  are  unstable  and, 
like  isovalerianic  acid  itself,  are  likely  to  prove  inactive  (Kochmann).  Perhaps 
valvyl,  valerianic  acid  diethylamide,  is  the  best  of  these  substitutes  for  the 
crude  drug.  It  appears  to  act  as  a  mild  hypnotic  and  sedative. 

BIBLIOGRAPHY 

Albertoni:  Arch.  f.  exp.  Path.  u.  Pharm.,  1882,  vol.  15,  p.  248. 

Behrend,  Henri:  Lane.,  May,  1864,  p.  607. 

Bermann:  Therap.  Monatshefte,  April,  1910. 

Bilinski:  Therap.  Monatshefte,  February,  1910. 

Binz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5,  p.  109. 

Ellinger  u.  Kotake:  Med.  Klinik,  1910,  No.  38,  p.  1474. 

F6r6,  Herbert  et  Peyrot:   Compt.  rend  de  la  societe"  de  biol.,  1892,  p.  513. 

*  v.  Wyss a  attributes  the  toxic  effects  of  the  bromides  to  the  diminished 
chloride  content  of  the  blood  and  not  to  the  accumulation  of  the  bromides. 
According  to  this  view,  the  curative  action  of  the  free  administration  of  sodium 
chloride  is  due  not  to  the  removal  of  the  excess  of  bromides  but  to  the  making 
good  of  the  chloride  deficit. 


116  PHARMACOLOGY  OF  CENTRAL  NERVOUS  SYSTEM 

Fessel:  Miinchn.  med.  Woch.,  1899,  p.  1270. 

Frey,  E.:  Zeitschr.  f.  exp.  Path.  u.  Therap.,  1910,  p.  461. 

Grisar:    Inaug.-Diss.,    Bonn,    1873. 

Grunwald,  Zentralbl.  f.  Physiol.,  1908,  vol.  22,  No.  16. 

Homburger :  Therap.  d.  Gegenw.,  1904,  p.  302. 

Hondo:  Berl.  klin.  Woch.,  1902,  p.  205. 

Hoppe:  Zentralbl.  f.  Neurologic,  1906,  p.  994. 

Kionka:  Arch.  int.  de  Pharmacodynamie,  1904,  vol.  13,  p.  215. 

Kochinann:  Deutsche  med.  Woch.,  1904,  p.  57. 

Kross:  Arch.  f.  exp.  Path.  u.  Pharm.,  1877,  vol.  .6,  p.  1. 

KUlz,  B.:  Zeitschr.  f.  Biol,  1887,  vol.  23,  p.  460. 

Laudenheimer :   Neurol.  Zentralbl.,  1897,  p.  538. 

Laudenheimer :  Neurol.  Zentralbl.,  1910,  p.  461. 

Lowald:  Kriipelin's  psychophysische  Arb.,  vol.  1,  No.  4. 

Nencki  u.  Schoumow-Simanowsky :  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  34, 

p.  313. 

Pflaumer:  Diss.,  Erlangen,  1896. 

Richet  et  Toulouse:  Compt.  rend  de  1'acad.  des  sciences,  1899,  vol.  129,  p.  850. 
Vigouroux:  Gaz.  des  hfipitaux,  1864. 
Voisin:  Bull,  de  therapeut.,  1866. 

*v.  Wyss:  Arch.  f.  exp.  Path.  u.  Pharm.,  1906,  vol.  55,  p.  266. 
*v.  Wyss:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59,  p.  186. 


CHAPTER  III 

PHARMACOLOGY  OF  THE  SENSORY  NERVE-ENDINGS 

THE  end-organs  of  the  sensory  nerves  are  everywhere  exposed  to 
the  pharmacological  action  of  chemical  substances. 

STIMULATION  OF  THE  SENSORY  NERVES  expresses  itself  as  pain,  as  a 
feeling  of  heat  or  cold,  etc.,  which  often  excite  reflexes,  as,  for  example, 
when  stimulation  of  the  sensory  nerves  of  the  stomach  causes  vomiting 
or  when  irritation  of  the  trigeminal  terminations  in  the  nasal  mucous 
membrane  produces  sneezing.  With  the  corrosives,  the  stimulation 
of  the  sensory  nerve-endings  is  only  a  symptom  of  the  general  action 
on  all  tissues  which  results  in  the  death  of  the  cells.  There  are, 
however,  certain  substances,  such  as  veratrine,  which  exert  an  abso- 
lutely specific  action  on  these  organs. 

REFLEX  EFFECTS  OF  SENSORY  STIMULATION. — In  collapse  and  in 
narcotic  poisoning,  agents  stimulating  these  organs  are  frequently 
employed  to  produce  a  REFLEX  STIMULATION  OF  THE  DEPRESSED  RESPIRA- 
TORY AND  CIRCULATORY  CENTRES.  For  such  purposes  mechanical  (fric- 
tion, slapping,  etc.),  thermic,  or  chemical  irritation  of  the  skin  may 
be  employed.  As  chemical  irritants  or  stimulants  only  such  agents 
may  be  used  as  penetrate  the  horny  epidermis  with  sufficient  rapidity 
to  reach  the  sensory  end-organs,  volatile  substances,  such  as  mustard 
oil  or  acetic  ether,  being  best  adapted  for  such  purpose.  Reflexes 
from  sensory  irritation  without  doubt  play  an  important  role  in 
producing  the  effects  caused  by  the  subcutaneous  injection  of  cam- 
phor and  of  ether,  especially  in  the  latter  case.  Olfactory  stimu- 
lation, as  by  ammonia,  and  stimulation  of  the  taste,  as  by  the  ethers 
of  wrines  with  strong  bouquet,  are  other  examples  of  sensory  stimula- 
tions, which  reflexly  affect  the  respiration  and  circulation. 

LOCAL  ANESTHESIA 

This  depends  on  the  feasibility  of  temporarily  depressing  the 
excitability  of  sensory  nerve-endings  without  permanently  damaging 
them,  and  in  recent  years  its  field  of  usefulness  has  been  steadily 
widened. 

Local  anaesthesia  may  be  induced  by  suppressing  the  excitability 
of  the  sensory  nerve-endings,  "TERMINAL  ANESTHESIA,"  or  by  prevent- 
ing the  conduction  of  nervous  impulses  in  the  nerve-trunks,  "NERVE 
BLOCKING.  ' '  The  blocking  of  the  centripetal  sensory  fibres  may  occur 
at  any  point  between  the  point  at  which  the  posterior  roots  enter  the 
cord  and  the  terminal  end-organs.  When  it  is  the  more  delicate  ter- 
minal nerve-fibres  which  are  affected,  it  is  difficult  to  distinguish  the 
effects  of  such  action  and  those  resulting  from  depression  of  the 

117 


118     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

terminations  of  the  nerves.  [As  a  matter  of  fact,  both  the  terminal 
organs  and  the  terminal  fibres  are  usually  affected  together. — TR.] 

Anesthetization  of  the  sensory  organs  may  be  produced  by  either 
physical  or  chemical  action.  Interruption  of  sensory  conductivity  by 
COMPRESSION  is  the  oldest  known  method  of  causing  anaesthesia.  The 
"going  to  sleep"  of  the  extremities,  with  the  resulting  paraesthesia 
and  numbness,  which  is  caused  by  accidental  compression  of  nerve- 
trunks  against  bone,  is  a  common  experience,  and  is  an  illustration 
of  anaesthesia  by  compression.  In  former  times  surgeons  frequently 
induced  anaesthesia  by  tightly  ligaturing  an  extremity.  [Infiltration 
anaesthesia  (see  below)  depends  wholly  or  in  part  on  the  effects  of 
compression  of  the  sensory  terminal  fibres  and  organs. — TR.]  Neu- 
ralgic pain  may  often  be  alleviated  temporarily  by  pressure  on  the 
trunk  of  the  nerve  affected. 

Anaesthesia  may  also  be  induced  by  producing  a  LOCAL  ANEMIA.  An 
example  of  this  is  the  anaesthesia  which  soon  follows  the  ligation  of  a 
large  vessel,  such  as  the  crural  artery,  the  terminal  sensory  organs 
being  the  first  structures  affected,  while  the  nerve-trunks  retain  their 
excitability  for  a  long  time,  even  after  complete  interruption  of  the 
blood  supply.  Anaemia  alone,  however,  does  not  induce  anaesthesia 
quickly  enough  for  practical  purposes,  but  the  application  of  the 
Esmarch  bandage  favors  local  anaesthesia  by  causing  both  compression 
and  anaemia.  As  will  be  seen  later,  both  compression  and  anaemia, 
induced  in  various  ways,  are  of  much  value  in  augmenting  and  aiding 
the  action  of  cocaine  and  similarly  acting  drugs. 

LOCAL  ANESTHESIA  BY  COLD. — Extreme  cold  can  also  render  unex- 
citable  both  the  terminations  and  the  trunks  of  the  sensory  nerves, 
as  is  evidenced  by  the  well-known  fact  that  the  extremities  become 
insensitive  when  exposed  to  ice  and  snow. 

James  Arnott,  in  1849,  was  the  first  to  make  a  systematic  use  of  cold  for 
the  induction  of  local  anaesthesia.  His  method  consisted  in  applying  a  mixture 
of  ice  and  salt  to  the  skin  of  the  part  to  be  anaesthetized.  Richet,  in  1859, 
employed  the  cold  resulting  from  the  evaporation  of  ether  for  the  purpose  of 
anaesthetizing  the  skin,  and  Richardson,  in  1866,  improved  the  technic  by  intro- 
ducing the  ether  spray. 

The  lower  the  boiling  point  of  the  evaporating  fluid  the  more 
intense  is  the  cooling  of  the  skin,  and,  therefore,  ETHYL  CHLORIDE, 
which  boils  at  12.5°  C.,  freezes  the  skin  much  more  rapidly,  and  for 
this  purpose  has  almost  completely  superseded  ether.  Mixtures  of 
ethyl  chloride  with  the  gaseous  METHYL  CHLORIDE,  which  boil  at 
2-0°  C.,  have  been  introduced  and  appear  to  have  advantages  as 
means  of  rapidly  freezing  tissues.  "Anaesthyl  Bengue"  and 
' '  metaethyl  Henning  ' '  are  two  such  preparations. 

When  exposed  to  low  temperatures,  the  smooth  muscles  and  the 
vessels  of  the  skin  first  contract  and  the  skin  becomes  pale,  but  on 
longer  exposure  reddens.  If  the  temperature  be  reduced  far  enough 


LOCAL  ANAESTHESIA  119 

to  freeze  the  skin,  it  suddenly  becomes  white  and  hard,  the  blood  flow 
ceases,  and  the  sensory  nerves  lose  their  excitability,  so  that  the  tissues 
become  insensitive.  The  anaesthesia  is  the  combined  result  of  the 
cold  and  the  anosmia.  Too  long  continuation  of  the  freezing  may 
result  in  gangrene.  At  the  start,  too  rapid  freezing  causes  quite  sharp 
pain,  but  gradual  freezing  and  thawing  are  painless.  The  pain  preced- 
ing the  anaesthesia  is  therefore  less  with  the  ether  spray  than  when 
ethyl  chloride  is  used.  [With  reasonable  care  freezing  with  ethyl 
chloride  is  practically  painless. — TB.] 

A  thorough  freezing  with  complete  anaesthesia  is  attainable  only  in 
the  skin,  for  the  penetration  of  the  effects  of  cold  is  limited  in  tissues 
freely  supplied  with  blood.  Consequently,  the  more  hyperaemic  mucous 
membranes  may  be  from  inflammation,  the  more  incomplete  is  the 
anaesthesia  from  cold.  In  spite  of  these  drawbacks,  freezing  of  the 
surface  often  renders  good  service  when  small  incisions  are  to  be  made 
or  an  abscess  opened.  Especially  is  this  the  case  in  dental  practice. 

LOCAL  AN/ESTHESIA  BY  CHEMICAL  AGENTS 
Until  Roller,  in  1884,  made  known  the  anaesthetic  action  of  cocaine, 
local  anaesthesia  was  induced  only  by  .the  methods  mentioned  above, 
and  practically  the  only  method  used  was  that  based  on  freezing. 
The  possibility  of  electively  influencing  the  sensory  nerves  by  chemical 
substances  was  for  the  first  time  demonstrated  by  the  action  of  cocaine. 
[Aconite  and  other  drugs,  however,  had  long  been  used  to  produce 
relative  local  anaesthesia. — TB.] 

Any  substance,  which  reacts  chemically  with  the  constituents  of  a 
sensory  cell,  necessarily  causes  a  change  in  the  constitution  of  its 
protoplasm  and  affects  its  function  in  some  degree  and  manner. 
Therefore  all  substances,  which,  as  a  part  of  their  general  destructive 
action  on  the  tissues,  possess  strong  chemical  affinities  for  the  con- 
stituents of  protoplasm,  cause  at  first  violent  stimulation  of  the  sensory 
elements,  or  pain,  and  later  insensibility  or  permanent  destruction  of 
their  function.  Consequently,  true  corrosives  cannot  be  utilized  to 
induce  anaesthesia.  As,  however,  the  sensory  end-organs  are  especially 
susceptible,  they  are  affected  by  very  weak  concentrations  of  the 
general  cell  poisons, — e.g.,  by  agents  precipitating  proteids.  In  this 
manner  certain  COBBOSIVES  in  relatively  great  dilution  may  induce  local 
anaesthesia  without  necessarily  harming  other  tissue  elements.  CAB- 
BOLIC  ACID  is  such  a  substance,  which  readily  penetrates  the  skin,  in 
proper  dilutions  causing  first  burning  and  later  insensibility.  Dress- 
ings saturated  with  1-2  per  cent,  carbolic  acid  solutions,  when  left 
in  contact  with  the  skin,  produce  a  local  anaesthesia,  but  they  may  also 
cause  gangrene. 

A  large  majority  of  the  substances  which  react  to  any  degree  with 
the  protoplasm  of  the  peripheral  sensory  nervous  elements  paralyze 
or  anaesthetize  these  only  after  first  causing  irritation  and  pain.  A 


120     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

typical  example  of  such  substances  is  ammonia,  which,  although  it 
specifically  paralyzes  motor  nerve-endings  (Qrutzner),  first  stimulates 
exposed  sensory  nervous  elements  and  afterwards  produces  a  marked 
anaesthetic  effect  (Gradenwitz) .  Such  substances  which  cause  first 
local  pain  and  later  local  anaesthesia  are  very  numerous,  and  have 
been  named  by  Liebreich  "AN^STHETICA  DOLOROSA.  " 


The  Effects  of  Anisotonic  Solutions. — On  account  of  its  rich  supply 
of  sensory  terminal  organs,  the  human  skin  is  the  tissue  most  suitable 
for  testing  the  effects  of  this  procedure  (Heinze,  Braun  *).  Solutions 
at  the  temperature  of  the  body  are  injected  into  the  skin,  causing  pale 
wheals  to  rise  above  the  surrounding  skin  (Schleich).  When  thus 
applied,  distilled  water  causes  first  pain  and  later  insensibility,  which 
may  last  for  a  quarter  of  an  hour.  Addition  of  salt  lessens  both  the 
primary  pain  and  the  anaesthesia,  while  0.9  per  cent.  NaCl  solutions, 
which  are  isotonic  with  the  tissues,  can  be  injected  without  causing 
pain,  but  as  the  concentration  is  increased  above  0.9  per  cent,  the 
primary  pain  and  the  later  anaesthesia  increase  progressively.  These 
effects  are  due  either  to  the  swelling  up  of,  or  the  abstraction  of  water 
from,  the  tissue  cells,  which  is  caused  by  the  hypotonic  or  hypertonic 
solution,  the  former  giving  off  water  to  and  swelling  up  the  cells, 
the  latter  abstracting  it  from  the  cells  and  causing  them  to  shrivel  up 
or  shrink.  These  effects  of  such  solutions,  which  can  be  closely  fol- 
lowed in  vegetable  cells,  in  the  erythrocytes,  and  in  other  readily 
isolated  cells,  also  occur  in  the  nerve-cells.  Braun 's  V  observations — 
that  the  "indifferent  point,"  where  the  least  effect  was  produced, 
was  found,  with  solutions  of  very  different  substances,  always  to  coin- 
cide with  concentrations  isotonic  with  the  blood — indicate  clearly  that, 
quite  aside  from  the  chemical  effects  of  different  salts,  acids,  bases, 
and  organic  substances,  the  physical  Influence  of  inhibition  or  of 
abstraction  of  water  can  affect  the  function  of  the  sensory  cells.  This 
fact  is  of  importance  in  connection  with  all  injections  into  the  tissues, 
and  for  this  reason  Braun  insists  on  the  use  of  osmotically  indifferent 
solutions  when  inducing  infiltration  anaesthesia  by  Schleich' s  method. 
Only  in  this  way  may  the  pain  due  to  the  swelling  or  shrinking  of  the 
nerve-cells  be  avoided  and  the  pure  cocaine  effects  be  obtained.  [In 
infiltration  anaesthesia,  pressure  also  plays  some  role. — TR.] 

COCAINE 

In  contrast  to  the  large  number  of  substances  belonging  to  the 
group  of  the  "  anaesthetica  dolorosa  "  is  the  relatively  small  number 
of  substances  which  exert  an  elective  action  on  the  peripheral  sensory 
elements,  and  which  possess  the  power  of  causing  a  paralysis  without 
any  marked  stimulation  of  these  elements.  Cocaine  was  the  first  drug 
known  to  possess  such  action,  but  since  its  introduction  a  number  of 


COCAINE 


121 


drugs  have  been  discovered  or  synthetized  which  produce  similar  effects 
and  resemble  it  more  or  less  closely  in  their  chemical  structure. 

Cocaine,  first  prepared  in  1860  by  Wohler  and  his  pupils,  occurs  in  the 
coca  leaves  in  the  proportion  of  about  %  per  cent.  From  the  rather  insoluble, 
readily  crystallized  alkaloid,  soluble  salts  may  be  prepared,  of  which  the  hydro- 
chlorate  alone  is  used.  It  is  an  ester  of  complex  structure,  resembling  atropine 
in  its  constitution.  On  boiling  with  acids  or  alkalies,  it  splits  up  into  benzoic 
acid,  methyl  alcohol,  and  the  base,  ecgonine,  which  closely  resembles  tropine,  a 
base  which,  with  tropaic  acid,  results  from  the  decomposition  of  atropine.  The 
foundation  of  both  the  bases  is  a  double  ring,  which,  it  may  be  assumed,  is. 
formed  by  the  combination  of  a  pyrrolidin  ring  with  a  piperidine  ring.  Ecgonine 
is  tropine  carbonic  acid.  The  close  constitutional  relationship  between  cocaine 
and  atropine  is  well  shown  in  the  accompanying  graphic  formulae. 


C< 


N(CH3) 


-CH- 


SoC 

XC\OH 


Tropine. 


-CH2 


COOH 
H 


\  /H 

N(CHs)  >C\ 

\OH 


-CH2 

Ecgonine. 


•^j 

j 


(CH3) 


,COOCH3 
~H 

/H 

>C\ 
\0. 


Cocaine,  benzoylecgonine  methyl  ester. 

Benzoylecgonine  has  no  local  anaesthetic  action  for  the  typical  cocaine 
actions  develop  only  when  this  substance  is  esterfied,  as,  for  example,  by  methy- 
lation.  Its  ethyl  ester  and  other  homologous  substances  act  like  cocaine  (Pauls- 
son).  The  pharmacological  activity  of  the  drug  depends  also  on  the  presence  in 
the  molecule  of  the  benzoyl  radical,  for,  when  other  acid  radicals  are  substituted, 
the  anaesthetizing  action  is  weakened  or  destroyed. 

SOURCE. — Cocaine  is  obtained  from  the  leaves  of  Erythroxylon 
coca,  a  plant  indigenous  in  South  America,  especially  in  Peru  and 
Bolivia,  where  it  was  held  to  be  a  sacred  object  and  was  valued  as  an 
indispensable  stimulant  (Genussmittel).  The  leaves  mixed  with  ashes 
or  lime  are  chewed  by  the  natives,  who  attribute  the  most  wonderful 
effects  to  this  practice,  claiming  that  it  increases  the  bodily  powers 
and  renders  one  more  eager  for  work  and  more  cheerful.  Especially, 
however,  they  believe  it  to  render  one  more  capable  of  great  exertion 
without  fatigue  and  of  resisting  hunger  and  thirst.  These  effects  have 
been  confirmed  by  the  observations  of  many  travellers.  Such  reports 
led  to  repeated  investigations  of  the  coca  leaves  in  European  lands, 
but  at  first  only  negative  results  were  obtained,  as  the  investigators 
attempted  only  to  determine  whether  the  coca  leaves  acted  as  a  means 
of  lessening  combustion  in  individuals  who  took  their  usual  nour- 
ishment. 


PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

*•• 

HISTORICAL. — Therapeutically  the  most  important  property  of 
cocaine  is  its  paralytic  action  on  the  sensory  nerve-endings.  Step  by 
step  the  induction  of  local  anaesthesia  by  the  use  of  cocaine  has  been 
logically  developed  and  has  acquired  a  constantly  increasing  impor- 
tance for  general  surgery,  until  to-day  it  represents  an  extremely 
valuable  supplement  to  general  anaesthesia. 

The  history  of  the  evolution  of  the  knowledge  and  use  of  cocaine  is  a  very 
interesting  example  of  the  slowness  with  which  an  important  fact  may  be  recog- 
nized and  of  how,  after  a  discovery  has  been  made,  a  long  time  may  elapse  before 
its  true  significance  is  appreciated.  Wohler,  who  was  the  first  to  prepare  cocaine 
in  pure  form,  in  his  description  of  its  properties,  wrote  of  it:  "It  tastes  bitter 
and  affects  the  nerves  of  the  tongue  in  a  peculiar  fashion,  so  that  for  a  time  the 
place  of  application  is  benumbed  and  almost  without  feeling."  The  local  anaes- 
thesia from  chewing  the  leaves  was  also  noted  long  ago  (de  Marie  1862,  Scherzer 
1865),  while  Moreno  y  Mays  in  1868  and  v.  Anrep  in  1880  demonstrated  the  local 
anaesthetic  action  in  animals,  and  the  latter  author  demonstrated  on  himself 
that,  by  subcutaneous  injection  of  this  drug,  the  skin  could  be  rendered  insensi- 
tive to  a  pin  prick.  However,  it  was  only  after  the  epoch-making  communication 
of  the  Viennese  oculist,  Roller,  who  in  1884  demonstrated  its  practical  value,  that 
ophthalmology,  laryngology,  and  other  branches  of  surgery  quickly  adopted  it. 

GENERAL  PHARMACOLOGICAL  ACTION. — Cocaine  is  a  general  proto- 
plasmic poison,  which,  if  absorbed  in  sufficient  amounts,  first  affects 
the  central  nervous  system.  If,  however,  it  is  applied  locally  to  the 
tissues  and  brought  in  contact  with  nerve-endings  and  fibres,  its  first 
action  is  that  of  suppressing  the  function  of  the  sensory  nerve  elements. 

It  is  of  fundamental  importance  for  the  local  action  of  cocaine  that, 
in  contrast  to  most  alkaloids,  ITS  SALTS  VERY  READILY  PENETRATE  INTO 
LIVING  CELLS  and  thus  easily  spread  into  the  tissues.*  On  account  of 
the  horny  nature  of  its  outer  coating,  human  skin  is  impermeable  to 
cocaine,  but  all  living  cells  readily  absorb  it,  and  thus  when  applied  to 
the  surface  of  intact  mucous  membranes  it  readily  reaches  the  sensory 
nervous  elements.  The  skin  of  the  frog  behaves  toward  it  similarly,  on 
account  of  its  numerous  glands  and  the  fact  that  it  is  constantly  moist 
and  able  to  give  off  or  take  up  gases  and  aqueous  solutions.  This 
animal  is,  therefore,  especially  adapted  for  the  demonstration  of  the 
anaesthetic  power  of  cocaine  (Gradenwitz) . 

Local  An&sthetic  Action. — In  the  "spinal"  frog  (one  in  which  the  higher 
portion  of  the  central  nervous  system  is  destroyed)  reflexes  follow  promptly 
on  sensory  stimulation  of  the  skin,  for  example  on  the  application  of  Ve  per  cent. 
HC1.  If,  however,  the  skin  of  one  leg  has  been  bathed  with  a  solution  of  cocaine, 
this  leg  is  withdrawn  from  the  acid  much  later  than  the  other,  and  with  suffi- 
ciently long  bathing  with  cocaine,  even  the  strongest  irritation  with  acid  fails 
to  produce  a  reflex  movement,  for  the  local  anaesthesia  is  absolute.  This  experi- 
ment succeeds  even  better  after  abolition  of  the  circulation  throughout  the  body, 
for  then  there  is  no  danger  of  absorption  of  enough  cocaine  to  affect  the  central 

*  According  to  Gros,  cocaine  salts  do  not  themselves  penetrate  the  living 
cells,  but  the  free  base  is  set  free  by  hydrolytic  action  and  enters  the  cells.  Conse- 
quently, the  more  strongly  the  salts  of  the  different  local  anaesthetics  are  dissoci- 
ated the  more  powerfully  do  their  solutions  act.  Gros,  therefore,  for  certain 
purposes  recommends  the  bicarbonate  of  novocaine  as  superior  to  other  salts 
formed  by  it  with  the  strongest  acids.  (See  p.  130.) 


COCAINE  123 

nervous  system.  The  behavior  of  the  other  leg  which  responds  normally  to  irri- 
tation demonstrates  that  the  failure  of  reflex  movements  is  not  due  to  a  paralysis 
of  the  cord,  and  the  normal  motor  reaction  of  the  cocainized  leg  when  the  other 
leg  is  stimulated  proves  that  the  motor  nerves  are  not  affected. 

Besides  those  of  the  algesic  nerves  the  nerve-endings  of  certain 
other  sensory  nerves  are  paralyzed,  as  for  example  those  of  the  nerves 
for  taste,  touch,  and  smell  (Zwardemaker),  while  reflexes  from  the 
mucous  membranes,  for  example  from  the  conjunctiva,  are  suppressed 
by  its  local  application.  If  ammonia  be  held  under  a  rabbit's  nose, 
under  normal  conditions,  the  respirations  cease  in  the  expiratory 
phase,  as  a  result  of  a  reflex  originating  in  the  trigeminal  endings  in 
the  nasal  mucous  membrane.  As  cocainization  of  the  nasal  mucous 
membrane  prevents  this  reflex  (Loewy  u.  Miiller),  it  has  been  sug- 
gested that  the  analogous  disturbing  reflexes  occurring  during  adminis- 
tration of  the  general  anaesthetics  be  prevented  by  a  preliminary 
cocainization  of  the  nasal  mucous  membrane.  For  operations  on  the 
larynx  and  in  the  nose  and  pharynx,  suppression  of  the  reflexes  is  often 
of  as  much  importance  as  is  the  suppression  of  the  pain  sense. 

The  anaesthetic  action  of  this  drug  on  the  nerve-endings  and 
smaller  branches  is  also  readily  demonstrable  in  open  wounds 
(Grutzner}.  Best  of  all,  however,  it  can  be  shown  in  the  skin,  by  the 
method  mentioned  on  page  120,  where  1  part  in  20,000  in  0.9  per  cent. 
NaCl  solution  destroys  the  sensibility  of  the  wheals  for  a  considerable 
time.  The  duration  of  the  anaesthesia  increases  with  the  concentration 
employed,  lasting  for  15  minutes  with  1  per  mille,  and  for  25  minutes 
with  1  per  cent,  solutions  (Braun,  Heinze).  The  anaesthesia  is  pre- 
ceded by  pain  lasting  a  short  time,  only  when  more  concentrated  solu- 
tions are  employed. 

ANESTHESIA  BY  NERVE  BLOCKING. — Cocaine  is  able  to  penetrate 
through  the  medullary  sheath  of  nerve-trunks  and  to  suppress  their 
conductivity  so  that  the  region  innervated  is  rendered  anaesthetic 
(REGIONAL  ANESTHESIA).  The  thinner  the  connective-tissue  sheaths 
of  the  sensory  nerves,  the  more  susceptible  are  they  to  this  blocking. 
Therefore,  the  finer  terminal  nerve-fibrils  are  scarcely  less  susceptible 
to  cocaine  than  are  the  nerve-endings.  As  the  drug  penetrates  more 
slowly  into  the  larger  nerve-trunks,  a  relatively  high  concentration 
is  necessary  for  their  anaesthetization  when  the  injection  is  made  in 
their  neighborhood  (perineural  injection),  but  with  endoneural  injec- 
tion even  quite  dilute  solutions  quickly  induce  anaesthesia. 

ELECTIVE  ACTION  ON  SENSORY  FIBRES. — Cocaine  acts  electively  on 
the  sensory  fibres,  for,  when  a  solution  is  applied  to  a  mixed  nerve,  the 
sensory  fibres  are  more  affected  than  the  motor  (Alms). 

After  1  minute  the  conductivity  of  the  sensory  fibres  of  the  frog's 
sciatic  is  abolished,  while  for  some  time  longer  motor  conductivity 
is  unaffected  (Kochs).  Dixon  has  confirmed  this  in  the  rabbit,  and 
Santesson  has  shown  that  contact  for  15  to  18  minutes  with  a  5  per 


124     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

cent,  solution  of  cocaine  so  completely  abolishes  sensory  conductivity 
of  the  nerves  that  even  the  strongest  tetanizing  stimulus  peripherally 
to  the  point  of  cocaine  application  produces  no  reflexes,  although  the 
motor  conductivity  remains  unaffected  for  about  one  hour  longer.  It 
is  thus  evident  that  not  only  the  terminal  organs  of  motor  and  sensory 
nerves  react  differently  to  various  drugs, — e.g.,  to  curare  and  cocaine, — 
but  that  the  two  types  of  nerve-fibres  show  a  similar  difference  in  their 
pharmacological  reactions.  Another  example  of  such  difference  is 
their  behavior  toward  ammonia,  which  stimulates  motor  fibres  hardly 
at  all  but  which  stimulates  sensory  fibres  more  powerfully  than 
either  NaOH  or  KOH  (Griitzner). 

Differences  in  the  Pharmacological  Reactions  of  Different  Kinds  of  Nerve- 
fibres. — It  might  be  possible  to  explain  the  difference  in  the  reactions  of  these 
two  types  of  fibres  by  assuming  that  a  different  degree  of  susceptibility  to  stimu- 
lation is  a  characteristic  of  their  respective  terminal  organs,  as  a  consequence 
of  which,  that  minimum  stimulation  of  the  sensory  fibres  which  would  be  sufficient 
to  produce  an  effect  in  the  central  reflex  mechanism,  would  be  greater  than  that 
necessary  to  cause  an  effective  stimulus  to  pass  down  the  motor  nerves  to  their 
terminal  organs.  More  briefly  expressed,  we  might  assume  a  higher  threshold 
value  for  stimulation  of  sensory  nerves  than  for  that  of  motor  nerves.  However, 
Dixon  has  shown  that  cocaine  exerts  a  selective  action  on  the  fibres  of  the  vagus 
also,  abolishing  the  conductivity  of  the  centrifugal  cardio-inhibitory  fibres  and 
leaving  unaffected  the  centripetal  fibres  connected  with  the  respiratory  and  vaso- 
motor  centres.  Moreover,  the  centrifugal  vasodilator  fibres  are  more  rapidly 
depressed  by  cocaine  than  are  the  vasoconstrictors. 

A  difference  in  the  reaction  of  the  different  types  of  fibres  must,  therefore, 
be  conceded.  Moreover,  the  greater  susceptibility  to  cocaine  manifested  by  the 
sensory  fibres  is  only  the  maximal  expression  of  a  general  law,  for  these  two  kinds 
of  fibres  exhibit  a  similar  behavior  toward  the  general  anaesthetics  (Pereles  u. 
Sachs,  Joteyko  u.  Stefanowska)  and  also  toward  aconitine  (Dixon).  As  a 
matter  of  fact,  the  same  law  holds  good  for  the  behavior  toward  drugs  of  the 
sensory  and  motor  elements  of  the  cord  and  brain,  for  ether,  chloroform,  etc., 
paralyze  the  sensory  side  of  the  spinal  reflex  arc  and  the  sensory  portion  of 
the  cerebrum  before  the  motor  excitability  disappears  (see  p.  57  ff).  It  appears, 
therefore,  that  all  sensory  nervous  elements  are,  as  a  rule,  more  readily  depressed 
by  chemical  reagents  than  are  the  motor  elements. 

ACTION  ON  OTHER  TISSUES. — Although,  as  shown  above,  cocaine 
electively  poisons  the  sensory  nerve-endings  and  fibres,  it  never  per- 
manently damages  the  other  tissue  cells  unless  too  concentrated  solu- 
tions are  applied.*  Other  local  anaesthetics  closely  related  to  cocaine, 
such  as  members  of  the  orthoform  group  and  stovaine,  are  not  so  free 
from  such  side  actions. 

ACTIONS  ON  THE  VESSELS. — These  are  the  only  organs  besides  the 
nerves  which  are  markedly  affected  by  the  local  action  of  cocaine. 
They  are  strongly  constricted,  and  thus  the  blood  supply  at  the  point 
of  application  is  markedly  diminished.  Under  its  influence  hypercemic 
and  swollen  mucous  membranes  become  pale  and  the  swelling  dimin- 
ishes or  disappears.  This  vasoconstricting  action  of  cocaine  is  often 
of  great  value,  as  for  example  by  rendering  sinuses  and  cavities  lined 
with  mucous  membrane  (such  for  example  as  the  nares)  more  accessible 

*  [The  cornea  is  especially  likely  to  be  damaged  by  too  concentrated  solu- 
tions.—TE.] 


COCAINE  125 

for  surgical  procedures.  The  anaemia  also  reinforces  the  anaesthetizing 
action  of  cocaine  by  retarding  its  absorption  from  the  tissues  into  the 
blood,  and  thus  keeping  it  for  a  longer  time  at  the  point  of  application. 
The  great  influence  on  the  induction  of  local  anaesthesia  which  is 
exerted  by  variations  in  the  blood  supply  of  the  tissues  is  well  shown 
by  the  fact  that  inflammatory  hypergemia  of  the  eye  renders  its  anaes- 
thetization  by  cocaine  much  more  difficult,  and  may  in  fact  entirely 
prevent  it.  On  this  account,  the  addition  of  epinephrin  to  the  cocaine 
solutions  often  greatly  augments  the  local  anaesthetic  action.  A  num- 
ber of  the  substitutes  for  cocaine  do  not  possess  this  vasoconstricting 
power,  while  some  of  them  directly  counteract  the  vasoconstricting 
action  of  epinephrin.  Cocaine's  superiority  in  this  particular  over 
many  of  its  substitutes  is  a  point  of  much  practical  importance. 

SYSTEMIC  ACTION. — In  systemic  poisoning  by  cocaine  the  depression 
of  the  sensory  nerve-endings  is  not  observed.  It  cannot,  therefore,  be 
considered  as  comparable  to  a  drug  possessing  a  "curare  action"  on 
the  sensory  nerve-endings,  for,  when  equally  distributed  throughout 
the  body  by  the  blood,  these  nerve-endings  are  not  the  first  elements  to 
be  affected,  but,  on  the  contrary,  the  central  nervous  system  is  the 
first  organ  to  be  affected.  Only  by  the  local  application,  which  brings 
the  cocaine  in  relatively  high  concentration  in  direct  contact  with  the 
sensory  nerve-endings  and  trunks,  is  it  possible  safely  to  abolish  the 
function  of  these  nervous  elements.  The  great  susceptibility  of  the 
central  nervous  system  is  responsible  for  the  toxic  effects  which  are 
observed  in  case  too  large  amounts  of  cocaine  are  applied  and  absorbed. 

The  action  on  the  central  nervous  system  consists  in  a  primary 
stimulation  and  a  secondary  depression  of  certain  tracts,  regions,  and 
functions,  while  others  are  depressed  from  the  start.  In  the  higher 
laboratory  animals,  very  small  doses  cause  the  appearance  of 
symptoms  of  excitation  of  the  cerebral  cortex,  great  restlessness,  hal- 
lucinations, and  uncontrollable  motor  activity.  In  man  also,  larger 
but  not  too  large  doses  (maximal  dosage  0.05  gm.  per  dose,  0.15  gm. 
per  diem)  [few  American  authors  would  consider  0.05  gm.  (=  5/6  gr.) 
a  permissible  dose. — TR.]  cause  confusion,  tendency  to  laughing,  etc., 
a  cocaine  ' '  Rausch, ' '  *  and  finally  delirium.  This  stimulating  effect 
on  the  cortex  no  doubt  is  one  of  the  reasons  why  coca  leaves  are  used 
in  South  America  as  a  stimulant  or  means  of  enjoyment  (Genussmit- 
tel),  while  the  suppression  of  sensations  of  hunger,  emphasized  in  all 
reports  concerning  this  custom  of  the  South  American  natives,  is  doubt- 
less due  to  the  blunting  of  the  sensibility  of  the  nerves  of  the  stomach. 

THERAPEUTICALLY  cocaine  has  been  administered  internally  to 
alleviate  gastric  pain  and  to  relieve  nausea  of  gastric  origin.  In 
conditions  of  mental  depression,  and  especially  during  the  withdrawal 
of  morphine,  attempts  have  been  made  to  utilize  the  power  of  stimu- 

*  Rausch  is  the  German  equivalent  of  the  slang  term  "  jag." 


126     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

lating  the  cortex  possessed  by  small  doses  of  cocaine.  It  was,  however, 
quickly  apparent  that  the  danger  of  habituation  was  equally  as  great 
with  cocaine  as  with  morphine,  and  perhaps  greater,  and  that  the 
therapeutic  use  of  cocaine  in  such  cases  led  to  a  cocaine  habit. 

TOXICOLOGY 

Toxic  ACTION  IN  ANIMALS. — In  warm-blooded  animals  the  first 
stage  of  poisoning  by  cocaine  is  characterized  by  restlessness,  excite- 
ment, and  motor  activity,  followed  by  clonic  convulsions  and  uncon- 
sciousness. The  pulse  is  accelerated  (accelerator  stimulation),  the 
blood-pressure  raised,  the  pupils  dilated  (stimulation  of  sympathetic 
nerve-endings),  and  the  body  temperature  is  increased.  In  dogs  it 
may  be  shown  that  these  convulsions  are  of  cortical  origin,  for  Fein- 
berg  and  Blumenthal  found  that  they  did  not  occur  after  previous 
extirpation  of  the  cortex,  nor  were  they  to  be  seen  in  new-born  puppies 
in  which  the  cortical  tracts  are  unexcitable.  The  convulsive  stage  is 
followed  by  a  paralytic  stage,  with  deep  coma,  loss  of  sensibility  and 
power  of  moving,  disappearance  of  the  reflexes,  and  finally  by  death 
due  to  paralysis  of  the  respiratory  centre  [and  also  of  the  vasomotor 
centres. — TR.]. 

The  symptoms  of  POISONING  IN  MAN  vary  with  the  dose  and  espe- 
cially with  the  rapidity  of  absorption.  When  very  toxic  doses  are 
gradually  absorbed,  the  poisoning  is  characterized  by  unconsciousness, 
convulsions,  and  dyspnoea.  At  the  start  the  preponderance  of  exci- 
tation may  cause  maniacal  behavior  or  epileptiform  convulsions,  with 
extreme  pallor,  dilated  pupils,  and  exophthalmos.  When  large  enough 
doses  are  very  rapidly  absorbed,  as  occurs  when  strong  solutions 
are  applied  to  eroded  mucous  membranes,  the  poisoning  may  develop 
with  very  few  symptoms,  the  victims  suddenly  fainting  and  becoming 
extremely  pale  and,  after  convulsions  lasting  but  a  short  time,  dying 
within  a  few  minutes.  With  rapid  absorption,  such  as  may  occur  after 
subcutaneous  injection,  as  little  as  0.05  gm.  may  cause  serious  poisoning. 

The  insufficient  recognition  of  the  fact  that  the  rapidity  with  which  cocaine 
is  absorbed  varies  markedly  according  to  the  method  of  application  and  the 
condition  of  the  mucous  membranes  has  led  to  a  belief  that  different  individuals 
exhibit  a  very  different  susceptibility  to  this  drug.  Many  cases  of  apparent 
idiosyncrasy  should,  however,  be  interpreted  as  due  solely  to  especially  rapid 
absorption,*  as  has  been  emphasized  by  Braun.* 

THE  TREATMENT  OF  ACUTE  COCAINE  POISONING  is  purely  sympto- 
matic. While  anaesthetics  or  narcotics  may  be  employed  to  control 
the  convulsions,  it  must  not  be  forgotten  that  their  administration 
augments  the  danger  from  the  paralysis  which  develops  at  a  later  stage. 
With  threatening  cessation  of  respiration,  artificial  respiration  should 
be  instituted.  It  goes  without  saying  that,  whenever  possible,  the  effort 

*  See  in  this  connection  the  relationship  between  the  actions  of  cocaine  and 
epinephrin,  pp.  159,  575). 


COCAINE  127 

should  be  made  to  prevent  the  further  absorption  of  the  poison.  In 
a  case  where  the  drug  has  been  injected  into  an  extremity,  this  is  best 
accomplished  by  checking  the  circulation  here  by  a  tight  bandage, 
and  after  its  introduction  into  any  of  the  body  cavities  by  washing 
them  out  in  the  endeavor  to  remove  any  portions  not  yet  absorbed. 

AVOIDANCE  OF  RAPID  ABSORPTION. — The  poisonous  effects  on  the 
central  nervous  system  occur  only  when  the  drug  is  present  in  the 
blood  in  a  certain  concentration,  which  need  never  be  attained  when 
the  drug  is  administered  for  its  local  effects,  if,  by  use  of  proper 
methods,  the  drug  is  so  administered  as  to  permit  a  gradual,  and  to 
prevent  a  too  rapid,  absorption.  Under  these  conditions  such  portions 
of  the  drug  as  enter  the  circulation  are  excreted,  and,  what  is  still 
more  important,  that  portion  which  remains  for  a  sufficient  time  in 
contact  with  the  tissues  is  destroyed  or  altered  by  them. 

DISTOXICATION. — The  rabbit  after  receiving  a  poisonous  dose  of  cocaine 
excretes  no  unaltered  cocaine,  while  the  dog  excretes  only  5  per  cent,  of  the 
amount  administered  ( Wiechowski ) .  Anything  which  causes  a  retardation  of 
the  absorption  and  thus  secures  for  the  organs  time  to  distoxicate  the  amounts 
gradually  absorbed  is,  therefore,  of  the  greatest  service  in  lessening  the  danger  of 
poisoning.  This  has  been  demonstrated  by  Kohlhardt,  Klapp,  and  Kleine,  who 
injected  ordinarily  lethal  doses  of  cocaine  into  the  leg  of  a  rabbit  after  pre- 
viously tightly  applying  a  rubber  tube  about  the  extremity.  Under  these  con- 
ditions the  longer  the  constriction  was  maintained  the  more  mild  was  the  course 
of  the  poisoning.  In  an  entirely  similar  manner,  otherwise  fatal  doses  of  cocaine 
may  be  injected  without  danger  if  the  paths  of  absorption  are  closed  by  adding 
to  the  solution  epinephrin,  our  most  powerful  vasoconstricting  agent.  In  such 
case  the  cocaine  leaves  the  tissues  very  slowly,  as  they  have  thus  been  rendered 
nearly  bloodless,  and  enters  the  circulation  only  gradually. 

PRINCIPLES  GOVERNING  THE  ADMINISTRATION  OF  COCAINE 

So  long  as  the  entrance  into  the  blood  of  cocaine  and  its  distoxi- 
cation  keep  pace  with  each  other,  relatively  large  amounts  may  be 
administered.  If  this  be  borne  in  mind,  the  theoretical  basis  for  the 
different  methods  of  administration  is  readily  arrived  at.  The  indi- 
cation is  to  apply  the  cocaine  in  sufficiently  concentrated  form  to  the 
peripheral  nervous  elements  which  are  to  be  anaesthetized,  and  to  keep 
it  there  long  enough  to  prevent  its  too  rapid  absorption.  This  indi- 
cation is  met  mainly  in  two  ways.  First,  by  using  the  weakest  solution 
which  will  produce  a  complete  anaesthesia  and  augmenting  its  effect  by 
bringing  it  in  intimate  contact  with  the  nerve-endings  and  prolonging 
the  period  of  its  contact  with  them.  These  are  essentially  the  prin- 
ciples involved  in  infiltration  anaesthesia.  The  second  method  consists 
in  using  relatively  high  concentrations  but  limiting  their  action  to  the 
neighborhood  of  the  nerve-trunks.  With  both,  methods  the  addition 
of  epinephrin  to  the  cocaine  solutions  diminishes  the  danger  of  sys- 
temic poisoning. 

1.  SURFACE  ANAESTHESIA  of  the  mucous  membranes,  wounds,  etc., 
may  be  secured  by  simply  dropping  on  them  solutions  of  cocaine  or  by 
applying  the  solutions  with  a  brush  or  in  cotton  tampons  and  by 


128     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

similar  simple  methods.  Anaesthesia  thus  induced  is  a  terminal  one, — 
i.e.,  one  affecting  only  the  terminal  sensory  nervous  elements.  When 
the  solution  can  remain  for  only  a  short  time  in  contact  with  the  mucous 
membrane, — as,  for  example,  when  it  is  used  for  operation  on  the  nose 
or  throat, — as  a  rule,  concentrated  solutions,  10-20  per  cent.  [ ! !  TB.],* 
must  be  applied.  On  the  other  hand,  for  superficial  anaesthesia  of  the 
cornea  a  2  per  cent,  solution  is  sufficient.  As  a  solution  injected  into 
the  bladder  or  urethra  may  remain  longer  in  contact  with  the  mucous 
membranes,  2-5  per  cent,  solutions  are  strong  enough.  The  danger  of 
systemic  poisoning  increases  with  the  extent  of  the  mucous  membrane 
to  which  the  solution  is  applied  and  with  its  power  of  absorption,  and 
it  should  be  remembered  that  this  danger  is  the  greatest  when  the 
mucous  membrane  is  hyperaemic  and  especially  when  it  is  ulcerated. 
The  addition  of  epinephrin  to  the  solutions  retards  the  absorption 
without  lessening  the  depth  or  duration  of  the  anaesthesia. 

In  the  Eye. — The  tissues  of  the  eye  present  such  favorable  con- 
ditions for  the  absorption  of  the  anaesthetic  that  in  two  minutes 
after  dropping  in  a  little  2  per  cent,  solution  complete  insensi- 
tiveness  is  secured.  Accompanying  this  are  dilation  of  the  pupil, 
protrusion  of  the  eye,  and  widening  of  the  palpebral  fissure,  all  due 
to  stimulation  of  the  sympathetic. 

2.  HYPODERMIC  AND  ENDERMIC  INJECTIONS. — Originally  1  to  5  per 
cent,  solutions  were  used  for  subcutaneous  injections.  Here  the  anes- 
thesia is  in  part  a  terminal  one  and  in  part  dependent  on  blocking 
of  the  conducting  fibres.  As  cocaine  is  very  rapidly  absorbed  from 
the  subcutaneous  tissues  when  its  absorption  is  not  artificially  pre- 
vented,— as,  for  example,  by  an  Esmarch  bandage, — the  use  of  such 
concentrated  solutions  is  almost  more  dangerous  than  a  chloroform 
anaesthesia.  By  using  weaker  solutions  the  danger  from  absorption 
may  be  lessened  without  interfering  with  the  induction  of  complete 
local  anaesthesia. 

INFILTRATION  ANAESTHESIA  (Schleich)  consists  in  infiltrating  the 
skin  over  the  region  to  be  incised  by  means  of  endermal  injections 
of  cocaine  solutions  and  then  infiltrating  the  lower  layers  one  after 
another.  When  the  solution  is  thus  brought  into  such  intimate  contact 
with  the  nerve-endings  in  the  field  of  operation,  a  satisfactory  anaes- 
thesia may  be  obtained  by  the  use  of  very  dilute  solutions  which  are 
just  strong  enough  to  anaesthetize  the  nerve-endings,  but  the  anaesthesia 
does  not  extend  beyond  the  infiltrated  area,  for  the  dilute  cocaine 
solution  is  efficient  only  at  the  point  of  application.  Schleich  recom- 
mended adding  to  the  0.1-0.2  per  cent,  cocaine  solution  only  0.2  per 
cent,  of  NaCl,  as  he  believed  that  the  hypotonicity  of  the  solution,  by 
causing  a  certain  amount  of  "imbibition  "anaesthesia  (see  p.  120),  would 
increase  the  effect  of  the  cocaine.  At  present  the  general  preference  is 

*  [The  careless  use  of  such  strong  solutions  may  readily  result  in  serious 
poisoning;  5111  of  20  per  cent.  sol.  =  1  gr. — TR.] 


COCAINE  129 

for  the  addition  of  0.8  per  cent.  NaCl,  as  advised  by  Braun  and 
Heinze,  with  the  object  of  avoiding  any  damage  to  the  tissues.  Schleich's 
solutions  contain  morphine,  but,  as  morphine  has  no  local  anaesthetic 
powers,  the  morphine  may  just  as  well  [or  better. — TR.]  be  injected 
before  or  after  the  operation. 

NERVE  BLOCKING. — Infiltration  anaesthesia,  however,  is  not  appli- 
cable in  all  conditions  or  situations.  For  example,  the  pain  caused 
by  the  numerous  injections  into  inflamed  tissues  prevents  its  use  under 
such  conditions.  When  such  is  the  case,  the  method  of  nerve  blocking 
(conduction  ancesthesia)  is  indicated,  a  method  in  which  the  danger 
of  systemic  poisoning  from  absorption  is  avoided  in  a  different  fashion. 
The  injection  of  a  small  quantity  of  a  solution  of  cocaine  under  the 
sheath  of  a  nerve  and  between  the  nerve-fibres  causes  an  immediate 
interruption  of  their  conductivity.  As,  however,  endoneural  injection 
usually  succeeds  only  when  the  nerve-trunk  has  first  been  exposed,  as  a 
rule  recourse  is  had  to  perineural  injection,  which  necessarily  demands 
a  stronger  solution  than  the  endoneural  application. 

This  nerve  blocking,  which  causes  a  REGIONAL  ANESTHESIA,  is  useful 
for  many  and  various  operative  procedures,  and  is  especially  adapted 
to  dentistry  (Peckert}.  It  is  also  particularly  adapted  to  the  anaes- 
thetization  of  fingers  and  toes,  where  its  effects  should  be  augmented 
by  the  use  of  epinephrin  or  tight  bandaging.  Even  major  operations, 
for  example,  those  involving  the  breast  or  the  thorax,  where  the  inter- 
costal nerves  may  be  "blocked,"  may  be  performed  painlessly  with 
the  aid  of  perineural  injections  (Hirschl). 

Circular  ancesthesia  according  to  Hackenbruch's  method  is  a  third 
method,  occupying  an  intermediate  position  between  infiltration  anaes- 
thesia and  regional  anaesthesia.  Here  the  tissues  surrounding  the  field 
of  operation  are  injected  in  a  continuous  irregular  circle  in  such 
fashion  as  to  block  all  the  sensory  nerves  supplying  the  part. 

3.  SPINAL  ANAESTHESIA. — Here  the  cocaine  acts  on  the  sheathless 
nerve-roots  as  they  emerge  from  the  cord  and  on  the  nerve-trunks  lying 
in  the  lumbar  dural  sac,  which  are  bathed  by  the  anaesthetizing  solu- 
tion, a  nerve  blocking  resulting. 

Medicine  owes  the  introduction  of  this  method  to  Bier,  of  Berlin. 
The  injection  in  man  of  0.005-0.03  gm.  of  cocaine  into  the  lumbar 
subdural  space  is  quickly  followed  by  paraesthesia,  and  soon  after- 
ward (in  5  to  10  minutes)  by  abolition  of  the  pain  sense  in  the  lower 
portion  of  the  body,  the  sensation  of  touch,  the  power  of  motion,  and 
the  reflexes  still  persisting.  With  further  development  of  the  action 
the  excitability  of  the  other  sensory  paths  is  abolished,  and  after 
still  larger  doses  there  occur  motor  weakness  and  paralysis  of  the 
lower  half  of  the  body.  Here  the  cocaine  clearly  acts  more  strongly 
on  the  sensory  than  on  the  motor  elements.  The  undesirable  and  often 
dangerous  side  actions,  which  have  not  infrequently  been  observed 
in  lumbar  anaesthesia,  are  all  probably  due  to  a  spreading  of  the 
9 


130     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

cocaine  inside  the  dura  up  along  the  cord  until  it  can  act  directly  on 
the  higher  vital  centres.  For  this  reason,  it  is  especially  important 
in  lumbar  anaesthesia  that  we  should  be  able  to  substitute  for  cocaine 
some  less  toxic  substance. 

By  a  new  method,  SACRAL  ANAESTHESIA  ( Stoeckel,  Lawen,  Schlimpert ) ,  in 
which  the  cocaine  solution  is  injected  into  the  sacral  canal,  the  attempt  has  been 
made  to  block  the  spinal  nerve-roots  after  they  emerge  from  the  dura.  This 
method  is  employed  chiefly  by  gynaecologists  for  special  indications.  As  is  self- 
evident,  it  is  necessary  to  use  stronger  solutions  here  than  when  they  are  injected 
intradurally,  otherwise  the  well-developed  nerve-sheaths  will  not  be  penetrated 
by  the  cocaine  in  effective  amounts.*  On  the  other  hand,  as  the  cord  is  protected 
from  the  drug  [and  as  the  cocaine  cannot  pass  up  alongside  of  the  cord  to  the 
vital  centres. — TR.],  the  side  actions  are  much  less  pronounced  (Schlimpert), 

BIBLIOGRAPHY 

Alms:   Dubois'  Arch.,  1886. 

v.  Anrep:  Pfliiger's  Arch,  1880,  vol.  21,  p.  38. 

Bier:   Zeitschrift  f.  Chirurgie,  1899,  vol.  51,  p.  361. 

'Braun:  Arch.  f.  klin.  Chir.,  1898,  vol.  57. 

2Braun:  Die  Lokalanasthesie,  Leipzig,  1905,  p.  49. 

3  Braun :  Die  Lokalanasthesie,  Leipzig,  1905,  p.  94. 

Dixon:   Journal  of  Physiology,  1905,  vol.  32,  p.  87. 

Ehrlich  u.  Einhorn:  Ber.  d.  Deutsch.  Chem.  Gesellsch.,  1894,  p.  1870. 

Feinberg  u.  Blumenthal:  Berl.  klin.  Woch.,  1887,  p.  166. 

Filehne:  Berl.  klin.  Woch.,  1887,  p.  107. 

Gradenwitz:  Inaug.-Diss.,  Breslau,  1898. 

Gros:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  80;  Miinchn.  med.  Woch., 

1910,  No.  39. 

Griitzner:  Pfliiger's  Arch.,  1894,  vol.  58. 
Heinze:  Virchow's  Arch.,  1898,  vol.  153. 
Hirshl:  Miinchn.  med.  Woch.,  1911,  No.  10. 

Joteyko  u.  Stefanowska:  Ann.  Soc.  roy.  des  sciences  m6d.,  Bruxelle,  vol.  10,  1901. 
Klapp:  Verhandl.  d.  Deutsch.  Chirurgenkongr.,  1904,  p.  260. 
Kleine:  Zeitschr.  f.  Hygiene,  1901,  p.  36. 
Kochs:  Zentralblatt  f.  klin.  Medizin,  1886,  vol.  7,  p.  793. 
Kohlhardt:  Verhandl.  des  Deutsch.  Chirurgenkongresses,  1901,  p.  644. 
Lawen:  Miinchn.  med.  Woch.,  1910,  No.  39. 
Liebreich:  Verhandl.  d.  7.  Kongr.  f.  inn.  Medizin,  1888,  p.  245. 
Loewy  u.  Miiller:  Miinchn.  med.  Woch.,  1903,  No.  15. 
Moreno  y  Mays:  Th£se  de  Paris,  1868. 
Peckert:  Die  zahnarztliche  Lokalanastesie,   etc.,   Habilitationsschr.,    Heidelberg, 

1905. 

Pereles  u.  Sachs:  Pfliiger's  Arch.,  1882,  vol.  52. 
Poulsson:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  301. 
Santesson:  Festschrift  fiir  Hammarsten,  1906. 
Schleich:  Verhandl.    d.    Deutsch.    Chirurgenkongr.,    1892;     Schmerzlose    Opera- 

tiohen,  Berlin,  1894,  p.  121. 

Schlimpert  u.  Schneider:  Miinchn.  med.  Woch.,  1910,  No.  49. 
Schlimpert:  Zentralblatt  f.  Gynakologie,  1911,  No.  12. 
Stoeckel:   Zentralbl.  f.  Gyn.,   1909,  No.  1. 
Tumass:   Arch.  f.  exp.  Path.  u.  Pharm.,  1886,  vol.  22,  p.  107. 
Wiechowski:   Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46,  p.  155. 
Wohler:   Annalen  d.  Chemie  u.  Pharmazie,  1860,  vol.  114,  p.  216. 
Zwardemaker,  cited  from  Braun:   Die  Lokalanasthesie,  p.  86. 

*  Novocaine  bicarbonate,  on  account  of  its  rapid  diffusibility,  is  especially 
adapted  for  this  method  (see  p.  122). 


SUBSTITUTES  FOR  COCAINE 


131 


SUBSTITUTES   FOR   COCAINE 

Starting  from  a  knowledge  of  the  constitution  of  cocaine,  by 
systematic  study  of  the  question  as  to  which  atom  groups  cause  the 
action  on  the  sensory  nerves  and  how  the  reciprocal  relation  of  these 
groups  affects  this  action,  it  has  been  possible  to  synthetize  a  consider- 
able number  of  substitutes  for  cocaine.  These  substitutes,  generally 
speaking,  possess  the  advantage  of  being,  when  used  in  equal  con- 
centration, cheaper,  less  toxic,  more  stable  in  solution,  and  of  being 
more  readily  sterilized,  but  they  are  also  less  powerful  anaesthetics 
than  cocaine.  They  can  often  replace  cocaine  in  practice  or  be  used 
as  adjuvants  to  it. 

CONSTITUTION  OF  COCAINE 

Strong  alkalies  decompose  cocaine  into  the  base  ecgonine,  methyl  alcohol, 
and  benzoic  acid. 


H2C 


H2C  CH 


COOH 


COOCHs 


H 


H 


% 


OH 


CH- 


Ecgonine. 

c<COOCHJ 


Methyl-ecgonine. 

H2C CH CH2 


COC.HS 


H,C 


Benzoyl-methyl-ecgonine  =  Cocaine. 

H2C CH- CH2 


Tropine. 


N(CH3) 


,H 
SO.COC6H5 


H2C CH CH2 

Benzoyl-tropine. 


H2C- 


CH C< 

CH2 

N(CH3) 


-CH2 


\c/H 
^\OH 

H 

O  •  COC«H8 


Benzoyl-pseudotropine  =  Tropacocainc. 


Methyl-ecgonine  is  inactive,  being  rendered  active  only  when  a  benzoyl 
radical  is  introduced  (Filehne,  Ehrlich  u.  Einhorn).  According  to  the  former 
author,  not  all  acid  radicals  produce  this  effect,  for  the  substitution  for  the 
benzoyl  radical  of  other  aromatic  acid  radicals  weakens  the  anaesthetic  activity, 
and  it  is  completely  abolished  by  the  substitution  of  aliphatic .  acid  radicals. 
Furthermore  the  discovery,  in  Javanese  coca  leaves,  of  TROPACOCAINE,  the  basic 
nucleus  of  which,  pseudotropine,  also  contains  the  benzoyl  group,  has  emphasized 
the  importance  of  this  group  for  the  specific  activity  of  these  substances.  As  a 
matter  of  fact,  Filehne  was  able  to  demonstrate  the  local  anaesthetic  powers  of 
other  benzoylated  alkaloids, — e.g.,  benzoyl-tropine.  From  these  facts  it  may  be 
concluded  that  the  specific  local  anaesthetic  action  is  due  to  the  combination 


132     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

of  certain  nitrogenous  basic  substances  with  the  benzoyl  radical.  If  the  basic 
complex  contains  a  COOH  group,  as  is  the  case  with  ecgonine,  its  acid  nature 
must  be  overcome  by  esterfication  with  a  methyl  or  ethyl  radical  or  with  some 
other  aliphatic  radical  (Poulsson). 

Einhorn's  S2,3  investigations  have  shown  that  local  anaesthetic  power  is 
a  common  property  of  all  basic  esters  of  benzoic  acid,  although  it  varies  in 
individual  cases  to  a  marked  degree.  While  many  other  aromatic  esters  also 
possess  this  power,  a  practical  importance  is  possessed  only  by  those  compounds 
which  exert  a  sufficient  degree  of  local  anaesthetizing  action  without  damaging 
the  tissues.  In  addition  a  sufficient  solubility  in  water  is  essential  for  their 
subcutaneous  and  intradural  administration. 

ORTHOFORM  SERIES. — Einhorn  and  Heinz,  by  investigating  the 
action  of  very  simply  constituted  derivatives  of  benzoic  acid, 
C6H5.COOH,  and  of  oxybenzoic  acid,  C6H4OHCOOH,  in  which  the 
very  complicated  nitrogenous  basic  radical  of  cocaine,  tropacocaine, 
etc.,  was  replaced  by  the  amido  group,  obtained  the  various  orthoforms. 
These  are  substances  which  are  but  slightly  soluble  in  water  and  which 
are  much  used  as  analgetic  dusting  powders. 


H 
C 


NH2 

4 


OH 

i 


OH 


net  /CH 


NH2 


COO 


CHs 

Benzoic  acid,  methyl  ester. 


HC,    JCH 

c 

COOCH3 


H( 


?        i 

V 


Para-amido-meta-oxy- 
benzoic  acid  methyl  ester, 
Orthoform. 


COOCHs 

Meta-amido-para-oxy- 
benzoic  acid  methyl  ester, 
Orthoform,  new. 


Other  numbers  of  this  group  are  the  more  soluble  NIRVANIN  and 
AN^ESTHESIN  (Dutibar,  v.  Noorden,  Spiess). 


NH2 

i 


HC 


CH 


N<H 

C 
HC/^CH 


2,  HC1 


HC .       ,  CH 
C 


OH-C 


CH 


^j 

(io 


p-amidobenzoic  acid  methyl 
ester,  Anaesthesia. 


OCH3  • 

The  hydrochloride  of  diethyl  p-amido-o-oxy- 
benzoic  acid  methyl  ester,  Nirvanin. 


NOVOCAINE. — Another  group  of  active  local  anaesthetics  have  been 
discovered  in  benzoyl  derivatives  of  the  amino-alcohols  which  were 
first  investigated  by  Einhorn.  Among  these  is  novocaine  (Einhorn4), 


SUBSTITUTES  FOR  COCAINE 


133 


which  appears  to  be  the  best  of  the  cocaine  substitutes  (Biberfeld, 
H.  Braun). 

NH4 


HCX    ^CB. 


!OO(CH2CH2N[C2H8]2)HCI 

The  hydrochloride  of  p-amido-benzoyl-diethyl- 
amidoethanol,  Novocsine. 

STOVAINE  (Fourneau),  ALYPIN  (Impens),  and  EUCAINE  also  belong 
to  this  series.  The  lactate  of  beta-eucaine  is  sufficiently  soluble  and  is 
much  used. 


HC 


H 
C 

/\ 


CH 


HC  v      ,  CH 
C     CH, 


COO  •  C- 


CH2  •  N(CH,)2  •  HC1 


The  hydrochloride  of  dimethylamidoben- 
soylpentanol,  Stovaine. 


coo-c- 


CH2  •  N(CH,)t 


CH2  •  N(CH,),  •  HC1 


The   hydrochloride  of  tetramethyldiamino- 
benzoylpentanol,  Alypin. 


H 
C 


HC 


HC 


CH 


CH 


I 
COO  - 


CH2    CH  •  CH, 

Trimethylbenzoyl-oxypiperidine  =  Eucaine  B. 
• 

COMPARATIVE    VALUES    OF    THE    SUBSTITUTES    FOR    COCAINE    AND 

THEIR  USES 

The  synthetic  cocaine  substitutes  may  be  sterilized,  are  fairly 
stable  in  solution,  and  are  all  less  toxic  to  the  central  nervous  system 
than  cocaine.  According  to  Brocqu,  tropacocaine  and  novocaine  are 


134     PHARMACOLOGY  OF  SENSORY  NERVE-ENDINGS 

only  half  as  toxic  as  cocaine  and  beta-eucaine  is  even  less  so,  but  their 
anaesthetic  action  is  also  weaker.  It  would  appear  that  the  toxicity 
for  the  central  nervous  system  runs  parallel  with  the  ancesthetic  action 
on  the  nerve-endings. 

TROPACOCAINE  (Chadbourne) ,  derived  from  the  Javanese  coca 
leaves,  while  less  toxic  is  also  much  more  evanescent  in  its  local  anaes- 
thetic action,  but  may  be  used  if  the  circulation  is  interrupted  by  a 
tight  bandage  or  by  pronounced  cooling.  On  account  of  its  relatively 
slight  toxicity,  it  has  recently  been  used  in  preference  to  cocaine  for 
spinal  anaesthesia.  In  the  eye  it  causes  slight  mydriasis  and  no 
irritation. 

BETA-EUCAINE  (Vinci)  is  also  much  less  toxic  than  cocaine,  its  toxic 
dose  being  three  times  as  large.  It  possesses  the  disadvantages  of 
being  somewhat  irritant  and  of  causing  local  hyperaemia. 

STOVAINE  is  much  used  for  intradural  anaesthesia,  especially  in 
Prance  (Challamel),  but  it  is  not  altogether  harmless  to  the  tissues, 
for,  in  the  presence  of  alkaline  carbonates,  the  insoluble  carbonate  of 
dimethylamidobenzoylpentanol  is  precipitated.  The  carbonate  of  its 
homologue,  ALYPIN,  being  soluble,  this  drug  does  not  cause  local  irri- 
tation (Braun2,  Lawen2). 

While  the  anaesthesia  produced  by  NOVOCAINE  is  more  evanescent 
than  that  produced  by  cocaine,  it  apparently  does  not  damage  the 
tissues  and  is  considered  by  many  to  be  the  best  of  the  cocaine  substi- 
tute (Brocqu,  Gros,  Braun?  Heinecke,  and  Lawen1). 

ORTHOFORM  and  others  of  this  group  are  not  substitutes  for  cocaine, 
but  are  rather  to  be  considered  as  complementary  substances  (Spiess). 
Most  of  them  being  rather  insoluble,  they  are  not  adapted  for  subcu- 
taneous use,  and  even  when  soluble,  as  is  the  case  for  example  with 
nirvanin,  their  anaesthetic  action  is  too  weak  for  them  to  be  of  value 
when  thus  administered.  On  the  other  hand,  orthof  orm  is  employed  as 
a  rather  insoluble  dusting  powder  for  wounds  and  ulcers.  As  it  pene- 
trates the  skin  and  mucous  membranes  with  difficulty,  it  relieves  pain 
only  when  brought  in  contact  with  exposed  nerve-endings,  in  which 
case  its  action  is  rather  prolonged.  It  should,  however,  be  used  cau- 
tiously, for  it  may  produce  other  undesirable  local  effects,  such  as 
O3dema,  eczema,  and  gangrene,  especially  when  used  in  the  treatment 
of  ulcers  of  the  leg.  It  also  transforms  oxyhaemoglobin  into  methaemo- 
globin,  even  in  a  dilution  of  0.02  per  cent.  It  should,  therefore,  not 
be  used  in  the  treatment  of  open  wounds  or  of  gastric  or  intestinal 
ulcers,  nor  should  it  be  injected  into  the  tissues  (Frohlich) . 

AJSLESTHESIN  is  employed  in  the  same  way  as  orthoform,  and 
causes  a  prolonged  local  anaesthesia,  apparently  without  producing 
the  harmful  effects  seen  with  orthoform.  In  the  form  of  its  p-phenol- 
sulphonate,  SUBCUTIN,  it  may  be  administered  subcutaneously,  but  is 
very  irritant  locally  (Braun3). 

The  differences  in  action  between  cocaine  and  its  above-mentioned 


SUBSTITUTES  FOR  COCAINE  135 

substitutes,  many  of  which  are  still  in  the  experimental  stage,  are  to 
some  degree  qualitative  as  well  as  quantitative,  for  when  applied  to 
mixed  nerves  all  of  them  do  not  appear  to  exert  so  elective  an  effect 
on  the  sensory  nerves  as  does  cocaine.  Stovaine,  for  example,  in  dilute 
solution  strongly  depresses  the  motor  nerve-endings  (Santesson).  In 
judging  of  their  value,  the  most  important  points  are  the  rapidity 
with  which  recovery  of  normal  function  occurs  after  their  employ- 
ment and  the  extent  to  which  they  cause  permanent  damage  to  the 
nerves.  In  these  respects  also  cocaine  apparently  is  superior  to  all 
its  substitutes  with  the  exception  of  novocaine  (Law en1).  In  addi- 
tion the  value  of  many  of  these  drugs  is  impaired  by  the  fact  that  they 
(e.g.,  eucaine  and  tropacocaine)  dilate  the  vessels,  and  thus  lessen  or 
prevent  (Ldwen  V)  the  favorable  effect  of  the  addition  of  epinephrin. 

BIBLIOGRAPHY 

Biberfeld:  Med.  Klinik,  1905,  No.  48. 

1  Braun,  H.:   Deutsche  med.  Woch.,  1905,  No.  42. 

2  Braun  H. :  Lokalanasthesie,  p.  132. 

3  Braun  H. :  Lokalanasthesie,  p.  130. 
Brocqu:   British  Med.  Journal,  March,  1909. 
Chadbourne:  Therapeut.  Monatsh.,  1892,  p.  471. 

Challamel,  A.:  Receuil  des  principaux  Memoires  cone,  la  Stovaine,  Paris,  1904. 
Dunbar:   Deutsch.  med.  Woch.,  1902,  No.  20. 
'Einhorn:  Liebig's  Annalen,  1900,  vol.  311. 

2  Einhorn:   Liebig's  Annalen,  1902,  vol.  325. 

3  Einhorn:   Liebig's  Annalen,  1908,  vol.  359. 

'Einhorn:  Ber.  d.  Deutsch.  Chem.  Gesellsch.,  1894,  vol.  27,  p.  1873. 

Ehrlich  u.  Einhorn:   Ber.  d.  Deutsch.  Chem.  Gesellsch.,  1894,  vol.  27,  p.  1870. 

Einhorn  u.  Heinz:   Miinchn.  med.  Woch.,  1897,  No.  34. 

Filehne:  Berl.  klin.  Woch.,  1887,  p.  107. 

Fourneau :  Compt.  .rend,  de  1'Acad.  des  sciences,  Paris,  Feb.,  1904. 

Frohlich,  A.:   Wiener  klin.  Woch.,  1909,  p.  1805. 

Gros:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  80. 

Heinecke  u.  Lawen:   Deutsche  Zeitschr.  f.  Chir.,  vol.  80,  p.  186. 

Impens:   Pfliiger's  Arch.,  1905,  vol.  110,  p.  21. 

1  Lawen:   Beitr.  z.  klin.  Chirurgie,  1906,  vol.  50,  p.  621. 

2 Lawen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  51,  p.  415. 

3 Lawen:  Deutsche  Zeitschr.  f.  Chir.,  1904,  vol.  74,  p.  163. 

v.  Noorden:  Berl.  klin.  Woch.,  1902,  No.  17. 

Poulsson:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  301. 

Santesson:  Festschr.  f.  Hammarsten,  1906. 

Spiess:  Miinchn.  med.  Woch.,  1902,  No.  39. 

Stoeckel:  Zentralblatt  f.  Gynakologie,  1909,  No.  1. 

Vinci:  Virchow's  Arch.,  1897,  vol.  149,  p.  217. 


CHAPTER  IV 

PHARMACOLOGY  OF  THE  VEGETATIVE  NERVOUS 

SYSTEM 

THUS  far  we  have  discussed  only  the  so-called  animal  nervous 
system,  and  the  manner  in  which  pharmacological  agents  may  in- 
fluence the  functions  of  its  various  parts,  the  sensory  nerve-endings, 
the  cerebral,  medullary,  and  spinal  centres,  and  the  efferent  nerves 
which  carry  motor  impulses  to  the  voluntary  striped  muscles.  We 
have  taken  these  up  in  a  particular  order,  believing  that  by  so  doing 
we  have  laid  the  foundation  for  a  clearer  understanding  of  the  manner 
in  which  pharmacological  actions  should  be  analyzed. 

THE  VEGETATIVE   NERVOUS   SYSTEM 

In  opposition  to  the  animal  nervous  system,  which  is  under  the 
control  of  the  will,  stands  the  so-called  vegetative  system,  the  efferent 
nerves  of  which  supply  those  organs  whose  functions  are  not  under  the 
control  of  the  will.  These  are  the  glands  and  the  organs  containing 
smooth  muscles,  such  as  the  viscera,  the  vessels,  the  smooth  musculature 
of  the  skin,  the  iris,  etc.  Physiologically  similar  to  these  organs  with 
smooth  muscle  are  certain  striated  muscles, — viz.,  those  of  the  heart, 
the  oesophagus,  and  the  penis,  and  in  certain  animals  the  iris,  which, 
in  the  birds  for  example,  is  composed  of  striped  muscle.  The  charac- 
teristic quality  of  the  innervation  of  all  these  tissues  is  due  to  the  fact 
that  their  functions,  although  they  may  be  influenced  through  the 
central  nervous  system,  are  able  to  continue  independently  of  it. 
The  nervous  system  which  innervates  them  possesses  a  certain,  although 
limited,  independence  of  the  central  nervous  system,  and  has  conse- 
quently been  named  by  Langley  the  AUTONOMIC  NERVOUS  SYSTEM. 
However,  we  shall  retain  the  name,  vegetative  nervous  system,  and  use 
the  term  autonomic  (parasympathetic)  only  for  that  portion  of  the 
vegetative  system  which  does  not  arise  from  the  sympathetic  trunk.* 

The  efferent  fibres  of  the  vegetative  nervous  system  reach  their 
terminal  organs — the  muscles  of  the  circulatory,  digestive,  and  sexual 
organs  and  the  glands,  etc. — through  nerves  which  emerge  from 
peripheral  nerve-ganglia.  While  vegetative  nerve-fibres  originate  in 
the  central  nervous  system,  it  is  characteristic  of  the  vegetative  nerves 
that  they  never  pass  directly  from  the  central  nervous  system  to  the 
periphery,  without  first  connecting,  during  some  portion  of  their 
course,  with  ganglion-cells. 

SYMPATHETIC  NERVOUS  SYSTEM. — Differing  both  anatomically  and 

*  [For  this  system  Langley  has  more  recently  suggested  the  name  parasympa- 
thetic, and  this  term  will  also  be  used  in  this  work. — Tu.] 

136 


ANATOMY  AND  PHYSIOLOGY  137 

embryologically,  as  well  as  physiologically  and  pharmacologically,  from 
the  other  vegetative  fibres  is  the  group  of  sympathetic  fibres,  which 
emerge  from  the  middle  portion  of  the  spinal  cord  in  the  thoracic  and 
the  first  4  or  5  lumbar  nerves  and  pass  through  the  white  rami  com- 
municantes  to  the  sympathetic  trunk  and  to  the  superior  and  inferior 
cervical  and  the  stellate  ganglia,  from  which  ganglia  they  join  the 
spinal  nerves  through  the  gray  rami  communicant es.  These  sympathetic 
nerves  supply  the  vessels,  glands,  and  smooth-muscled  organs  through- 
out the  body  and  form  a  homogeneous  portion  of  the  vegetative  nervous 
system.*  In  the  accompanying  diagram  (p.  139)  these  nerves  are 
colored  red. 

AUTONOMIC  OR  PARASYMPATHETIC  SYSTEM. — However,  almost  all 
these  organs,  as  indicated  by  the  nerves  colored  blue  in  the  diagram, 
also  receive  another  sort  of  vegetative  nerves,  some  of  which  arise 
from  the  brain  and  medulla,  and  others  from  the  sacral  cord,  and 
which  are  called  by  us  the  CRANIAL  and  the  SACRAL  AUTONOMIC  (para- 
sympathetic)  nerves.  Autonomic  nerves  also  arise  from  the  midbrain, 
which  run  in  the  oculomotorius  to  the  ciliary  ganglion,  from  which 
they  pass  as  the  short  ciliary  nerves  to  the  sphincter  of  the  iris  and  the 
ciliary  muscle. 

In  the  chorda  tympani  are  secretory  fibres  for  the  salivary  glands, 
and  vasodilator  fibres  for  the  oral  cavity,  which  are  autonomic 
nerves  arising  from  the  medulla.  The  facial  and  glossopharyngeal 
nerves  also  contain  secretory  and  vasodilator  fibres,  which  pass  into 
the  trigeminus  and  supply  the  oral,  nasal,  and  pharyngeal  mucous 
membranes.  Finally,  autonomic  fibres  emerge  from  the  medulla  oblon- 
gata  and  run  in  the  vagus  to  the  viscera.  These  are  the  cardio- 
inhibitory  fibres,  constrictors  for  the  bronchial  muscles,  motor  fibres 
for  the  oesophagus,  stomach,  and  intestine,  and  secretory  fibres  for  the 
stomach  and  the  pancreas.  This  autonomic  system  may  be  named  the 
cranial-bulbar  or,  briefly,  the  CRANIAL  AUTONOMIC  SYSTEM.  Its  influence 
is  most  powerful  at  the  oral  end  of  the  alimentary  canal  and  in  the 
neighboring  structures  of  the  head,  and  from  there  down  diminishes 
in  extent  and  intensity.  Near  the  anal  end  of  the  alimentary  canal  it 
is  replaced  by  the  SACRAL  AUTONOMIC  SYSTEM,  the  fibres  of  which  pass 
from  the  cord  in  the  first  sacral  nerve,  and,  as  the  nervus  pelvicus, 
supply  the  lower  portion  of  the  alimentary  canal — the  descending 
colon,  rectum,  and  anus — as  well  as  the  bladder  and  genital  organs. 

A  third  nervous  mechanism  controlling  the  automatic  movements 
of  the  hollow  viscera,  such  as  the  intestine,  has  received  from  Langley 

*  As  a  result  of  the  labors  of  Gaskell,  Langley,  and  others,  our  knowledge 
of  the  structure  and  function  of  the  sympathetic  and  of  the  other  autonomic 
systems  has  undergone  a  complete  transformation  in  recent  years.  The  following 
description  is  based  on  the  views  developed  by  Langley,  which  may  be  found  as 
described  by  him  in  Schaefer's  text-book  on  physiology,  1900,  vol.  2,  p.  516,  and 
in  Asher-Spiro's  Ergebn.  d.  Physiologic,  1903,  vol.  2,  p.  808.  The  nomenclature 
followed,  however,  is  the  one  indicated  above. 


138  PHARMACOLOGY:  VEGETATIVE  NERVOUS  SYSTEM 

the  name  of  the  ' '  ENTERIC  SYSTEM.  ' '  These  are  peripheral  automatic 
centres,  which,  however,  receive  impulses  from  the  central  nervous 
system  through  autonomic  and  sympathetic  fibres. 

All  the  sympathetic  nerves  form  a  physiological  unit,  and  every- 
where their  nerve-endings  exhibit  one  common  pharmacological  reac- 
tion (to  epinephrin).  According  to  Langley,  on  the  other  hand,  the 
cranial  and  the  sacral  autonomic  systems  belong  together  in  a  physio- 
logical sense.  This  physiological  relationship  is  most  strongly  demon- 
strated by  their  similar  reaction  to  a  number  of  drugs  and  poisons,  to 
which  we  will  later  turn  our  attention.  Pharmacologically  the  cranial 
and  sacral  autonomic  systems  exhibit  a  distinct  contrast  to  the  sympa- 
thetic system,  just  as  they  do  in  respect  to  their  functions,  and  this  too 
in  spite  of  the  fact  that  both  types  of  vegetative  nerves  appear  to  be 
essentially  similar  in  structure. 

However,  all  the  vegetative  nerves,  in  accordance  with  this  similar 
structure,  possess  one  pharmacological  reaction  in  common,  the  dis- 
covery of  which  was  a  decisive  step  toward  the  recognition  of  their 
true  nature.  This  is  their  reaction  to  nicotine,  which  exerts  an  elective 
action  on  one  particular  portion  of  all  vegetative  nerves.  In  accord- 
ance with  the  general  scheme  of  their  arrangement,  the  vegetative 
nerve-fibres,  unlike  those  of  the  animal  system,  never  pass  directly 
from  the  central  nervous  system  to  their  terminal  organs,  but,  after 
leaving  the  gray  matter  of  the  central  nervous  system,  pass  into  ganglia 
in  which  the  central  fibres  terminate,  coming  at  this  point  into  close 
relationship  with  the  ganglion-cells,  from  which  new  nerve-fibres  then 
pass  down  to  the  terminal  organs.  These  separate  fibres  are  conse- 
quently named  the  pre-ganglionic  and  the  post-ganglionie  fibres.  The 
course  of  the  vegetative  nerves  is  always  interrupted  in  a  ganglion, 
and  in  the  whole  course  of  the  nerve  only  in  a  single  ganglion,  where 
there  is,  as  it  were,  a  switching  of  the  impulse  from  the  pre-ganglionic 
to  the  post-ganglionic  fibres.  This  interruption  of  the  impulse  may 
occur  in  the  first  ganglion  through  which  the  nerve  passes, — for 
example,  in  one  of  the  vertebral  ganglia,  which,  like  the  spinal  ganglia, 
are  segmentally  arranged  in  the  sympathetic  trunk.  Other  vegetative 
fibres,  however,  pass  through  a  first  and  often  a  second  ganglion,  which 
may  be  interposed  in  their  path,  without  branching  in  them,  and 
terminate  only  in  more  peripherally  situated  prevertebral  ganglia, — 
for  example,  the  nerve  fibres  of  the  splanchnicus  terminate  in  the 
solar  plexus  and  those  of  the  pelvic  nerve  in  the  hypogastric  plexus, 
while  others  may  terminate  in  still  more  peripherally  lying  ganglia, 
which  are  situated  directly  in  the  terminal  organs. 

The  vertebral  ganglia,  with  the  exception  of  the  superior  and  inferior  cer- 
vical ganglia,  supply  the  vegetative  organs  of  the  skin  and  the  trunk  and  extremi- 
ties, which  include  the  glands,  the  vessels,  and  the  smooth  muscles  of  the  skin, 
while  the  prevertebral  ganglia  supply  exclusively  the  viscera.  The  stellate  and 
the  superior  cervical  ganglion,  which  may  be  looked  upon  as  resulting  from  the 
fusion  of  vertebral  and  prevertebral  ganglia,  supply  both  viscera  and  skin. 


140  PHARMACOLOGY:  VEGETATIVE  NERVOUS  SYSTEM 

COMMON  REACTION  TO  NICOTINE. — No  matter  at  what  point  the 
central  fibres  terminate  and  this  switching  occurs,  and  no  matter  what 
the  function  of  the  post-ganglionic  fibres,  whether  motor,  inhibitory, 
or  secretory,  nicotine  always,  after  a  primary  stimulation,  causes  a 
paralysis  of  this  relay  station,  or  ganglion.  This  is  the  general  rule 
to  which  there  are  no  exceptions,  although  the  different  ganglia  exhibit 
a  variable  degree  of  susceptibility  toward  this  poison  and  although 
greater  differences  are  exhibited  by  different  species  of  animals;  for 
example,  nicotine  acts  far  less  powerfully  on  these  ganglia  in  the  dog 
than  in  the  cat  or  rat. 

Langley,  by  applying  a  dilute  solution  of  0.5  per  cent,  of  nicotine  to  the 
separate  exposed  ganglia,  produced  a  localized  poisoning,  and,  using  this  method, 
was  able  to  employ  this  drug  as  the  means  of  determining  whether  an  efferent 
vegetative  nerve-fibre  passed  through  the  ganglion  in  question  without  joining 
it,  or  whether  at  the  poisoned  point  the  fibre  terminated  and  entered  into  a 
physiological  union  with  the  ganglionic  cells.  If  stimulation  of  the  nerve  at  a 
point  lying  centrally  to  the  ganglion  still  produced  the  same  effect  as  before  the 
application  of  the  poison,  it  was  clear  that  its  nerve-fibres  merely  passed  through 
the  ganglion,  but  if  such  stimulation  did  not  produce  such  effect,  it  was  evident 
that  the  nerve-fibres  in  question  terminated  in  this  ganglion,  and  that  the  post- 
ganglionic  fibres  arose  from  it.  By  means  of  this  method,  Langley  was  able 
to  demonstrate  the  interruption  of  numerous  sympathetic  and  cranial  and  sacral 
autonomic  nerves  in  their  various  vertebral  and  prevertebral  ganglia.  One 
example  may  serve  to  make  this  more  readily  understood.  Stimulation  of  the 
cervical  sympathetic  below  the  stellate  ganglion  causes  dilation  of  the  pupil, 
widening  of  the  palpebral  fissure,  and  alteration  of  the  calibre  of  the  vessels 
and  of  the  secretory  functions  of  the  cranial  mucous  membranes.  After  appli- 
cation of  nicotine  to  this  ganglion  the  same  stimulation  produces  no  vasoconstric- 
tion  in  the  upper  extremity,  but  still  produces  the  same  effects  in  the  eye  and  in 
the  cranial  mucous  membranes.  From  this  it  is  evident  that  the  vasomotor  nerves 
of  the  upper  extremity  enter  into  some  sort  of  a  union  with  the  ganglionic  cells, 
while  the  nerve-fibres  for  the  pupil  and  for  the  cranial  mucous  membranes  pass 
through  this  ganglion  and  do  not  find  their  relay  station  until  they  reach  the 
cervical  ganglia. 

After  the  injection  of  nicotine  into  the  circulation,  stimulation  of 
all  pre-ganglionic  fibres  is  ineffective,  while  stimulation  of  post-gan- 
glionic fibres  causes  all  the  usual  effects.  This  shows  that  the  nerve- 
fibres  and  their  peripheral  nerve-endings  remain  excitable  and  that 
nicotine  poisons  only  the  relay  stations  in  the  ganglia. 

THE  ANTAGONISTIC  FUNCTIONS  OF  THE  SYMPATHETIC  AND  AUTO- 
NOMIC OB  PARASYMPATHETIC  SYSTEMS. — The  action  of  the  nicotine  is 
exerted  on  all  the  ganglia  of  the  entire  vegetative  system,  whether  their 
fibres  originate  from  the  sympathetic  or  from  the  autonomic  system,  but 
otherwise  these  two  groups  of  vegetative  nerves  in  many  respects 
exhibit  an  antagonistic  physiological  and  pharmacological  behavior. 
In  this  connection  it  is  a  fact  of  very  great  importance  that  most  of 
our  organs  possess  a  double  innervation,  coming  on  the  one  hand  from 
the  sympathetic  system  and  on  the  other  from  the  cranial  or 
sacral  autonomic  (parasympathetic)  system,  and  that  almost  every- 
where, where  organs  are  thus  doubly  innervated,  this  double  •  inner- 


SYMPATHETIC  NERVOUS  SYSTEM  141 

vation  is  an  antagonistic  one,  the  stimulation  of  the  sympathetic 
fibres  causing  the  opposite  effect  from  that  produced  by  stimu- 
lating the  fibres  belonging  to  the  autonomic  system.  For  example, 
the  splanchnicus,  a  sympathetic  nerve,  inhibits  the  movements 
of  the  intestine,  while  the  parasympathetic  fibres  of  the  vagus  and  the 
sacral  fibres  of  the  pelvicus  excite  the  motor  activity  of  the  upper 
and  lowest  portions  of  the  intestines.  This  antagonism  is  also  evi- 
denced by  the  following  physiological  facts:  Thus,  the  dilator  of  the 
iris  is  innervated  by  the  sympathetic,  while  the  antagonistic  sphincter 
of  the  iris  is  innervated  by  autonomic  fibres  in  the  oculomotorius,  and 
the  cardio-inhibitory  fibres  of  the  vagus  are  opposed  by  the  sympathetic 
accelerans.  In  short,  almost  all  organs  for  which  a  double  inner- 
vation  from  both  systems  has  been  demonstrated  are  antagonistically 
influenced  through  these  systems.  There  exists,  however,  a  group  of 
organs, — viz.,  the  vessels  and  glands  of  the  skin — which,  so  far  as 
our  present  knowledge  goes,  appear  to  be  innervated  only  by  the 
sympathetic  system.  _ 

EPINEPHRIN  A  SPECIFIC  POISON  FOR  SYMPATHETIC  NERVE-ENDINGS. — 
The  different  physiological  behavior  of  the  two  vegetative  systems 
expresses  itself  also  in  their  reaction  to  pharmacological  agents,  there 
being  one  group  of  drugs  which  act  only  on  the  sympathetic  nerve- 
endings,  and  another  which  acts  on  all  the  various  autonomic  nerve- 
endings.  Thus,  epinephrin,  the  suprarenal  hormone,  excites  all  the 
nerve-endings  which  in  the  accompanying  diagram  are  colored  red, — • 
that  is,  it  always  produces  the  same  effects  on  the  various  organs  as 
are  produced  by  stimulation  of  their  sympathetic  nerve-fibres.  Owing 
to  this  action  on  the  sympathetic  nerve-endings,  epinephrin  causes 
vasoconstriction  in  all  vascular  systems  [except  the  pulmonary  and 
coronary  ? — TR.]  ,  strengthening  and  acceleration  of  the  heart-beat  simi- 
lar to  that  caused  by  stimulation  of  the  accelerans,  dilatation  of  the 
pupil  like  that  produced  by  stimulation  of  the  cervical  sympathetic, 
and  secretion  of  the  salivary  glands  in  so  far  as  these  glands  are  ren- 
dered active  by  stimulation  of  their  sympathetic  nerves. 

Where,  however,  sympathetic  fibres  are  inhibitory  in  their  func- 
tions,— for  example,  in  the  stomach  and  intestine,  or  in  the  bladder, — 
epinephrin  does  not  cause  a  stimulation,  but,  on  the  contrary,  an  inhibi- 
tion of  their  motor  functions.  Epinephrin  always  produces  the  same 
effect  as  the  stimulation  of  the  sympathetic  nerve  of  any  organ,  a  fact 
which  is  especially  strikingly  demonstrated  in  those  organs  in  which 
stimulation  of  the  sympathetic  nerves  causes  in  one  species  of  animal 
contraction  and  in  another  relaxation,  as  is  the  case  for  example  in 
the  bladder  (Elliot).  It  may,  therefore,  be  stated  that  epinephrin 
produces  excitation  only  on  those  vegetative  nerve-endings  which 
belong  to  the  sympathetic  system.* 

*  With  the  single  exception  of  the  sweat-glands  which  react  to  pharmaco- 
logical agents  as  if  autonomically  innervated. 


142  PHARMACOLOGY:  VEGETATIVE  NERVOUS  SYSTEM 

In  ERGOTOXIN,  a  substance  present  in  ergot,  Dale  has  discovered  another 
toxic  substance  which  also  exhibits  a  limited  elective  affinity  for  certain  of  the 
sympathetic  nerve-endings,  for  it  poisons  only  the  nerve-endings  of  those  fibres 
the  stimulation  of  which  causes  motor  activity,  and  produces  no  effect  on  those 
causing  inhibition.  After  large  doses  of  ergotoxin  a  stimulation  of  vasocon- 
strictor nerves  no  longer  causes  vasoconstriction,  the  accelerans  loses  its  influence, 
and  so  forth,  while  the  inhibitory  influence  of  the  splanchnicus  on  the  intestine 
or  of  the  sympathetic  nerves  on  the  bladder,  in  those  animals  in  which  they  inhibit 
this  organ,  remains  unaffected. 

SPECIFIC  POISONS  FOR  AUTONOMIC  OR  PARASYMPATHETIC  NERVES.— 
While  epjnjphrin  produces  no  effect  on  the  cranial  and  sacral  autono- 
mic  nerve-endings,  there  is  another  group  of  drugs  which  act  particu- 
larly on  these  organs,  leaving  the  sympathetic  nervous  system,  with  one 
exception,  entirely  unaffected.  The  chief  representatives  of  this  group 
are  atropine  on  the  one  hand  and  muscarine,  pilocarpine,  physostig- 
mine,  and  choline  on  the  other.  Of  these  muscarine  stimulates  and 
atropin  paralyzes  the  nerve-endings  of  the  autoiiomic  fibres  which  in  the 
diagram  are  colored  blue.  This  antagonism  holds  good  right  down  the 
line,  muscarine  causing  miosis,  and  atropine,  by  preventing  the  action 
of  the  autonomic  oculomotorius,  causing  mydriasis ;  on  the  heart  mus- 
carine producing  the  same  effect  as  stimulation  of  the  vagus,  while 
atropine  prevents  the  action  of  the  vagus  and  thus  enables  the  influence 
of  the  sympathetic  accelerator  fibres  to  gain  the  upper  hand,  mus- 
carine causing  contraction  and  atropine  relaxation  of  bronchial 
muscles.  Further,  muscarine  and  pilocarpine  cause  violent  contraction 
of  the  gastric  and  intestinal  muscles  and  of  the  smooth  muscles  of 
other  organs,  while  atropine  in  certain  dosage  abolishes  the  tone  of 
these  muscles.  Muscarine  and  pilocarpine  cause  secretion  in  all  true 
glands;  atropine  inhibits  it.  As  these  drugs  also  act  in  a  similar 
fashion  on  the  glands  of  the  skin, — although,  as  far  as  is  at  present 
known,  they  are  innervated  only  by  sympathetic  and  not  by  autonomic 
nerves, — we  have  here  an  apparent  exception  to  the  general  law  of 
their  behavior.  However,  one  can  almost  believe  that  this  exception  is 
actually  only  an  apparent  one,  and  that  it  will  be  explained  when  more 
has  been  learned  of  the  innervation  of  these  glands. 

The  points  at  which  these  different  drugs  act  are  not  completely 
known  in  all  their  details.  This  much,  however,  is  certain, — viz.,  that 
they  all  act  on  the  terminal  nervous  organs  of  the  autonomic  nerves, 
and  that  this  common  pharmacological  behavior  indicates  that  the 
different  nerve-endings  of  this  system  belong  together. 

Similar  pharmacological — which  is  the  same  as  to  say  similar  chemical — 
reactions  of  organs  indicate  a  homologous  chemical  structure,  and  consequently 
such  may  be  assumed  for  all  the  sympathetic  terminal  nervous  organs,  and 
also  for  all  autonomic  ones.  Moreover,  the  nerves  of  these  two  systems  appear 
to  differ  also  in  respect  to  their  points  of  origin  in  the  central  nervous  system, 
these  centres  being  also  characterized  by  certain  chemical  or  pharmacological 
reactions  which  are  characteristic  of  them.  Picrotoxin,  obtained  from  Indian 
berries  (Anamirta  paniculata),  in  addition  to  producing  other  effects,  stimu- 
lates all  the  cranial  and  sacral  autonomic  nerves, — the  oculomotorius,  the  chorda 
tympani,  the  vagus,  and  the  pelvicus, — this  action  being  not  peripheral  but  cen- 


VEGETATIVE  NERVOUS  SYSTEM  143 

tral  (Griinwald).  It  thus  appears  that  the  autonomic  centres  all  exhibit  the 
same  chemical  reaction.  This  may  not  be  said  of  the  sympathetic  central  organs 
with  the  same  general  application,  for  up  to  the  present  there  are  only  a  few 
facts  known  which  indicate  that  this  is  probably  the  case  (Jonescu). 

From  the  above  it  may  be  seen  that  nicotine  acts  on  all  the  ganglia 
of  the  entire  vegetative  nervous  system,  while  epinephrin  exerts  its 
action  only  on  the  sympathetic  nerve-endings.  Besides  the  above- 
mentioned  drugs  many  other  substances  act  on  the  separate  portions 
of  the  vegetative  system.  As,  in  all  doubly  innervated  organs,  the 
stimulation  of  one  system  and  the  depression  of  the  other  must  pro- 
duce similar  effects,  it  is  evident  that  the  same  alterations  of  the  func- 
tions of  these  organs  may  result  from  pharmacological  actions  exerted 
on  different  points.  Thus,  for  example,  dilatation  of  the  pupil  may  be 
produced  either  by  stimulation  of  the  sympathetic  nerve-endings  in 
the  iris  by  epinephrin,  or  by  paralysis  of  the  oculomotorius  nerve- 
endings  by  atropine,  or  the  action  of  the  heart  may  be  accelerated  as 
a  result  of  stimulation  of  the  accelerator  nerve-endings  by  large  doses 
of  caffeine,  or  by  paralysis  of  the  vagus  nerve-endings  by  atropine. 
It  is  thus  evident  that  unusually  numerous  and  complicated  pharmaco- 
logical actions  on  the  vegetative  nervous  system  are  possible. 

BIBLIOGRAPHY 

Dale:   Journ.  of  Physiol.,  1906,  vol.  34,  p.  163. 
Elliott:   Journ.  of  Physiol.,  1905,  vol.  32. 
Grunwald:   Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 
Jonescu:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 
Langley:  Journal  of  Physiology,  1898,  vol.  23,  p.  240. 


CHAPTER  V 

PHARMACOLOGY  OF  THE  EYE 
PHARMACOLOGICAL   REACTIONS   OF  THE  RETINA 

THE  light-sensitive  layers  of  the  retina — i.e.,  the  visual  cells  with 
their  rods  and  cones — transmit  their  impulses  to  the  layer  of  the  retinal 
ganglion-cells  through  the  bipolar  cells,  which  may  be  looked  upon  as 
corresponding  to  the  spinal  ganglion-cells,  while  the  retinal  ganglionic 
layer  may  be  considered  as  a  portion  of  the  gray  matter  of  the  central 
nervous  system  which  has  been  pushed  out  into  the  periphery  and  from 
which  impulses  pass  via  the  optic  nerve  into  the  brain,  just  as  im- 
pulses pass  from  spinal  ganglia  through  the  conducting  paths  up  into 
the  higher  portions  of  the  central  nervous  system. 

This  preliminary  statement  appears  necessary  in  order  that  we  may 
understand  why,  in  the  first  place,  many  toxic  substances  which  act  on 
the  retinal  ganglia  also  produce  changes  in  the  optic  nerve  which 
arises  from  them,*  in  apparent  contradiction  to  the  behavior  of  the 
centripetal  nerves  whose  sensory  terminal  organs  in  the  periphery  may 
be  damaged  without  its  being  necessary  that  the  nerve  itself  be  in- 
jured, and  why,  in  the  second  place,  the  retinal  elements  themselves 
are  acted  upon  by  pharmacological  agents  whose  preponderating 
actions  are  ordinarily  exerted  only  on  the  central  nervous  system. 

DRUGS  RELIEVING  RETINAL  HYPEEAN^ESTHESIA. — This  is  of  signifi- 
cance for  those  cases  in  which  the  susceptibility  of  the  retina  is  abnor- 
mally augmented  or  diminished  by  photophobia  or  by  retinal  ambly- 
opia.  Drugs  which  are  certainly  able  to  moderate  hyperaesthesia  of 
the  retina  in  photophobia  accompanied  by  severe  pain  are  apparently 
not  known.  According  to  Simpson,  if  the  eye  be  held  immediately 
above  chloroform  its  vapors  relieve  photophobia,  and  the  same  is  stated 
to  be  true  of  carbonic  acid  gas  (Einger-Thamhayn) . 

The  symptoms  of  photophobia  are  due  to  stimuli  which  reach  the  centres 
through  the  trigeminus.  They  may  occur  even  after  previous  section  of  the  optic 
nerve  and  in  the  totally  blind,  and  are,  therefore,  to  be  considered  as  due  to  a 
reflex  occurring  within  the  retina,  which  here  behaves,  as  it  were,  as  a  segment 
of  the  spinal  cord.  They  appear  to  be  analogous  to  the  algesias  and  hyperalgesias 
of  particular  regions  of  the  skin  which  have  been  described  by  Head  as  occurring 
in  diseases  of  the  viscera  whose  innervation  is  connected  with  the  same  segment 
of  the  spinal  cord  as  is  that  of  the  painful  cutaneous  area.  However,  this  pain 
resulting  from  bright  light  is  often  due  only  to  a  spasmodic  reflex  contraction 
of  the  sphincter  of  the  iris,  and  in  such  cases  it  disappears  when  atropine  or 
homatropine  is  instilled. 

*  In  this  connection,  among  others,  may  be  mentioned  the  amblyopias  due 
to  toxic  action  of  methyl  alcohol,  quinine,  felix  mas,  pelletierine,  and  probably 
also  in  part  those  due  to  tobacco,  ethyl  alcohol,  and  carbon  disulphide  (.Uhthoff). 

144 


RETINA  AND  IRIS  145 

DRUGS  AUGMENTING  RETINAL  EXCITABILITY. — On  the  other  hand, 
the  excitability  of  the  retinal  elements  may  be  certainly  augmented 
by  STRYCHNINE,  which,  as  we  know,  possesses  the  power  of  increasing 
reflex  excitability  in  general.  Sharpness  of  vision  of  both  the  normal 
eye  and  of  one  impaired  as  a  result  of  amblyopia  may  be  temporarily 
increased  by  this  drug.  This  action  takes  place  chiefly  in  the  periphery 
but  also  to  a  certain  extent  in  the  centres,  and  results  in  an  improve- 
ment in  the  power  of  differentiating  colors  (Dreser) .  This  effect  may 
be  produced  on  one  side  only  if  strychnine  be  injected  into  the  temple 
or  instilled  into  the  eye  (Filehne}.  It  is  just  as  difficult  to  determine 
whether  such  a  temporary  augmentation  of  the  excitability  of  the 
retinal  ganglionic  organs  can  be  of  value  in  diseases  of  the  eye  as  it 
is  to  judge  of  the  value  of  the  analogous  employment  of  strychnine 
in  motor  pareses. 

SANTONINE. — A  peculiar  alteration  of  the  perceptive  retinal  elements  of 
caused  by  the  anthelmintic  santonin.  About  one-half  hour  after  taking  this  drug, 
brightly  illuminated  objects  appear  violet,  and  a  little  later  yellow.  This  is 
due  to  a  primary  stimulation  followed  by  depression  of  the  retinal  cells  which  are 
susceptible  to  the  violet  rays  of  the  spectrum.  The  central  color  sense  (com- 
plementary perception  of  violet)  remains  (Knies). 

BIBLIOGRAPHY 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  33. 

Ellaby,  Miss:  Arch.  d'Ophthalm.,  1882,  vol.  2,  p.  532. 

Filehne:   Pfliiger's  Arch.,  1901,  vol.  83. 

Grafe-Samisch :  Handb.,  1901,  Literature. 

Knies:  Arch.  f.  Augenheilk.,  1898,  vol.  37. 

Simpson,  cited  from  Ringer-Thamhayn :   Handbuch,  1877. 

Uhthoff :  Ueber  die  Augenstorungen  bei  Vergiftungen,  Leipzig,  1901. 

PHARMACOLOGICAL  ACTIONS  ON  THE  IRIS  AND  THE 
CILIARY  MUSCLE 

We  possess  a  much  more  exact  knowledge  of  the  action  of  drugs 
on  the  motor  organs  of  the  internal  eye, — i.e.,  on  the  muscles  of  the 
iris  and  on  the  ciliary  muscle. 

The  iris  is  made  up  of  two  sets  of  muscles,  one  set  being  arranged  in  the 
form  of  a  ring  while  the  other  is  composed  of  radiating  muscle-fibres.  The  circu- 
lar muscle,  the  sphincter  of  the  iris,  is  innervated  by  the  autonomic  post- 
gangl ionic  fibres  coming  from  the  oculomotorius,  which  send  pre-ganglionic  fibres 
to  the  ciliary  ganglion.  The  antagonistic  radial  muscle,  the  dilator  of  the  iris, 
is  innervated  by  the  sympathetic  nerve  coming  from  the  superior  cervical  gan- 
glion, from  which  the  post-ganglionic  fibres  pass  to  these  muscles  alongside  the 
ciliary  ganglion  and  via  the  carotid  plexus. 

The  contraction  of  the  ciliary  muscles  narrows  the  ring  in  which  the  lens 
is  suspended  so  that  owing  to  its  own  tension  it  can  become  more  convex.  The 
ciliary  muscle  receives  the  impulses  which  produce  this  effect  through  the  cranial 
autonomic  fibres  of  the  oculomotorius,  just  as  does  the  sphincter  of  the  iris. 

It  is  claimed  by  Morat  and  Doyon,  and  denied  by  Heese  and  others,  that 

nervous   impulses  are   received  by  the  ciliary   muscle  through  the   sympathetic 

which  produce  the  antagonistic  effect  of  widening  this  ring  and  rendering  the 

lens  less  convex.    The  negative  results  of  the  last-named  authors  cannot,  however, 

10 


146 


PHARMACOLOGY  OF  THE  EYE 


be  considered  as  definitely  decisive,  because  the  range  of  accommodation  of  the 
animals  used  in  their  experiments  is  too  slight  (Heese,  Hess  u.  Heine). 

Certain  drugs  produce  in  both  of  these  muscles  stimulation  or  paralysis  as 
should  be  expected  from  their  different  nerve  supply. 

The  centres  of  the  autonomic  oculomotorius  which  lie  in  the 
cerebrum  may  be  affected  by  pharmacological  agents  so  as  to  produce 
changes  in  the  pupil,  asphyxia  for  example  causing  a  paralysis  of  these 
centres.  Consequently,  a  sudden  maximal  dilatation  of  the  pupil 
serves  as  one  of  the  latest  warnings  of  danger  of  asphyxia  in  the  course 
of  anesthesia. 

SUCH   DILATATION  OF   THE   PUPIL  OF   CENTRAL  CAUSATION,   DUE   TO   INHIBITION 

OF  THE  OCULOMOTOKIUS,  may  result  from  psychic  excitement,  such  as  a  sudden 
fright,  or  from  direct  electric  stimulation  of  the  cerebral  cortex  in  the  region 


FIG.  8. — Red,  sympathetic  nerves;  blue,  autonomic  or  paraaympathetic  fibres 
from  the  oculomotorius. 


of  the  gyrus  sigmoideus  or  of  the  basal  ganglia,  and  this  may  occur  when  either 
the  trigeminal  nerve,  which  contains  the  vasomotor  nerves  of  the  iris,  or  the 
superior  cervical  sympathetic  ganglia  or  the  cervical  cord  itself  has  been  severed. 
This  reflex  dilatation  of  the  pupil  can,  consequently,  be  explained  only  as  due 
to  a  weakening  of  the  tone  of  the  oculomotorius  centre, — i.e.,  as  due  to  the 
stimulation  of  a  central  inhibitory  mechanism  ( Braunstein ) .  If  this  inhibitory 
mechanism,  which  is  ordinarily  kept  active  by  all  sorts  of  sensory  stimuli, 
becomes  inactive  as  the  result  of  cutting  off  all  sensory  stimuli, — as,  for  example, 
in  natural  sleep  or  that  caused  by  chloral, — the  tone  of  the  oculomotorius  centre 
is  augmented  and  the  pupil  contracts. 


CENTRAL  MIOTICS  AND  MYDRIATICS  147 

In  all  probability  this  central  autonomic  inhibitory  mechanism  is  electively 
paralyzed  by  morphine,  even  in  moderate  doses  which  produce  hardly  any  anal- 
getic "effects.  Consequently  a  more  or  less  pronounced  miosis  is  a  constant  symp- 
tom of  the  action  of  morphine.  Atropine  overcomes  this  morphine  miosis 
promptlv,  but  cocaine,  whose  action  is  only  that  of  rendering  the  sympathetic 
nerve-endings  more  excisable,  hardly  alters  it  (personal  communication  of 
E.  Fuchs ) .  Both  of  these  facts  indicate  the  correctness  of  the  explanation  of  the 
morphine  miosis  given  here.  It  would  appear  that  the  autonomic  centre  of  the 
cardiac  vagus  is  affected  in  an  analogous  fashion,  and  this  is  probably,  therefore, 
an  explanation  of  the  slowing  of  the  heart  caused  by  morphine  (Danilewski  u. 
Lawrinowitsch).  This  hypothetical  inhibitory  centre  may  be  looked  upon  as  being 
a  controlling  mechanism  for  the  sympathetic  nerves,  which  acts  in  opposition 
to  and  is  opposed  by  corresponding  centres  of  the  cranial  autonomic  nerves  so 
that  they  maintain  a  combined  control  or  balance,  just  as  is  the  case  with  the 
motor  centres  controlling  the  agonistic  and  antagonistic  voluntary  muscles.  ( See 
p.  16  and  Fig.  3,  p.  17.) 

In  all  probability,  therefore,  the  miosis  of  sleep  and  of  morphine 
poisoning  is  due  to  a  markedly  augmented — i.e.,  uninhibited — tone  of 
the  oculomotorius  centre  which  normally,  in  the  waking  state,  is  under 
the  influence  of  strong  inhibitory  impulses  from  the  cerebral  cortex, 
the  corpora  quadrigemina,  and  the  corpora  striata  (Braunstein} . 

Miosis  due  to  excitation  of  this  autonomic  oculomotorius  centre  is  one  of 
the  symptoms  produced  by  the  action  of  certain  central  convulsants,  particularly 
picrotoxin  (Griinwald).  This  is  of  some  interest,  inasmuch  as  this  drug  elec- 
tively excites  not  only  the  centres  of  the  autonomic  oculomotorius  but  also  all 
other  centres  of  the  autonomic  nerves  known  to  us,  those  of  the  chorda,  vagus, 
pelvicus,  etc.,  from  which  the  conclusion  may  be  drawn  that,  like  their  terminal 
organs,  the  motor  centres  controlling  the  agonistic  and  antagonistic  voluntary 
muscles  have  a  common  chemical  structure. 

Mydriasis  due  to  paralysis  of  the  oculomotorius  centre  occurs  as 
a  pathognomonic  symptom  in  certain  poisonings, — for  example,  those 
caused  by  meat,  fish,  mussels,  cheese,  and  particularly  by  that  caused 
by  sausage,  the  so-called  botulismus.  Here,  however,  not  only  the 
autonomically  innervated  internal  muscles  of  the  eye,  the  iris  and  the 
ciliary  muscle,  but  almost  always  the  external  muscles,  as  well  as  the 
levator  palpebrge,  are  affected  so  that  ptosis  and  usually  double  vision 
result.  This  is  a  readily  recognized  difference  between  the  effects  of 
such  poisonings  and  of  all  other  poisonings  which  cause  a  mydriasis 
induced  peripherally  (Uhthoff). 

BIBLIOGRAPHY 

Braunstein:  Zur  Lehre  d.  Innervation  d.  Pupillenbewegung,  Wiesbaden,  1894. 

Danilewski  u.  Lawrinowitsch:   loc.  cit. 

Griinwald:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 

Heese:  Pfluger's  Arch.,  1892,  vol.  52. 

Hess  u.  Heine:   Grafe's  Arch.,  1898,  vol.  46. 

Uhthoff :  Ueber  die  Augenstorungen  bei  Vergiftungen,  Leipzig,  1901. 

MIOTICS  ACTING  IN  THE  PERIPHERY 

The  autonomic  nerve-endings  in  the  sphincter  of  the  pupil  and 
in  the  ciliary  muscle  are  stimulated  by  the  drugs  of  the  physostigmine 
group,  of  which  physostigmine  itself  is  the  most  important. 


148  PHARMACOLOGY  OF  THE  EYE 

PHYSOSTIGMINE  OR  ESERINE 

PHYSOSTIGMINE,  or  eserine,  is  an  alkaloid  occurring  in  the  calabar  bean,  the 
fruit  of  Physostigma  venenosum.  With  sulphuric  and  salicylic  acid  it  forms 
readily  crystallizable,  colorless,  hygroscopic  salts,  whose  aqueous  solutions  after 
a  time  acquire  a  red  to  dark  cherry-red  color,  as  the  result  of  the  formation  of 
an  inactive  oxidation  product,  rubreserine.  The  calabar  bean  contains  another 
alkaloid,  eseridine,  with  similar  action,  and  still  another,  calabarine,  which 
possesses  a  convulsant  action. 

MIOTIC  ACTION. — If  a  few  drops  of  a  1  per  cent,  solution  of  eserine 
be  instilled  into  an  eye,  after  about  20  minutes  the  pupil  becomes 
narrow  and  the  ciliary  muscle  begins  to  contract.  The  near  point  and 
far  point  of  vision  approach  each  other,  and  after  half  an  hour  the 
far  point  approximates  the  normal  near  point.  After  about  two  hours 
the  spasm  of  accommodation  passes  off,  but  the  pupil  remains  narrow 
for  a  considerable  time  longer.  At  this  time,  however,  the  accommo- 
dation is  still  more  excitable  than  normally  and  the  slightest  voluntary 
effect  produces  a  most  extreme  degree  of  accommodation  (Earner) . 

Apparently  the  action  of  eserine  on  the  pupil  could  be  explained 
just  as  well  by  a  paralysis  of  the  dilator  as  by  a  spasm  of  the  con- 
strictor mechanism  of  the  iris,  or  it  might  be  attributed  to  both  of  these 
effects  occurring  at  the  same  time.  However,  it  may  be  experimentally 
shown  that  the  dilator  of  the  iris  retains  its  excitability,  for,  if  the 
cervical  sympathetic  be  stimulated  in  an  animal  whose  pupils  are 
maximally  contracted  by  eserine,  they  dilate  in  normal  fashion.  This, 
however,  does  not  prove  that  the  tone  of  the  sympathetic  nerve-endings 
in  the  iris  has  not  perhaps  been  weakened  by  eserine.  This  is,  in  fact, 
probable,  inasmuch  as  apparently  every  stimulation  of  the  sphincters 
is  necessarily  accompanied  by  a  relaxation  of  the  dilators,  and  vice 
versa  (Way mouth  Reid}. 

The  point  at  which  eserine  acts  is  thus  seen  to  lie  in  the  sphincter 
of  the  iris  and  in  all  probability  in  the  terminal  organs  of  the  auto- 
nomic  oculomotorius,  for  under  certain  conditions  it  can  produce  con- 
traction of  the  pupil  even  after  section  of  the  short  ciliary  nerves  or 
after  removal  of  the  ciliary  ganglion,  but  it  no  longer  produces  this 
effect  if  sufficient  time  has  elapsed  since  their  section  to  permit  the 
nerve-endings  to  degenerate.  Defined  more  exactly,  its  action  does  not 
consist  in  a  direct  excitation  of  these  elements,  but  in  the  production 
of  a  very  marked  augmentation  of  their  excitability.  This  appears  to 
be  indicated  by  the  observations,  described  below,  on  the  lowering  of 
the  threshold  value  for  stimuli  which  is  caused  by  eserine.  It  is  also 
in  agreement  with  the  fact  that  after  previous  section  of  the  oculo- 
motorius,— i.e.,  after  abolition  of  stimuli  from  this  centre, — eserine 
produces  no  apparent  effects, — i.e.,  does  not  overcome  the  existent 
sympathetic  tone.  Only  after  section  of  the  sympathetic  is  it  effective 
and  able  to  narrow  the  pupil,  for  then  the  chemical  stimuli  furnished 
by  the  blood  are  sufficient  to  stimulate  the  terminal  organs  of  the 


MIOTICS  ACTING  IN  PERIPHERY 


149 


oculomotorius  if  they  have  been  rendered  over-excitable  by  eserine. 
It  is  important  to  emphasize  this  fact,  because  of  the  action  of  eserine 
in  similarly  increasing  the  excitability  of  the  other  autonomic  (para- 
sympathetic)  terminal  organs  (see  below). 

ACTION  ON  ACCOMMODATION. — This  action  of  eserine,  that  of  ren- 
dering the  oculomotorius  nerve-endings  in  the  ciliary  muscle  more 
excitable,  is  responsible  for  the  facilitation  of  accommodation  or  the 
spasm  of  accommodation  which  may  result  from  its  employment.  As 
a  result,  in  addition  to  rendering  it  difficult  or  impossible  to  see  clearly 
any  objects  lying  beyond  the  near  point,  eserine  causes  one  to  over- 


Zoriula  tense 

Iris  thickened  and  retracted 
FIG.  9. — Monkey's  eye  after  atropine  (Heine). 

estimate  their  size  (macropsia),  because,  on  account  of  the  slighter 
effort  at  accommodation  they  are  held  to  be  more  distant  and,  as  the 
angle  of  vision  remains  the  same,  they  are  held  to  be  larger. 

EFFECT  ON  INTRA-OCULAB  TENSION. — Another  result  of  the  action 
of  physostigmine  in  the  eye  is  much  more  important;  this  is  the 
diminution  of  the  intra-ocular  pressure  (Laqueur).  This  is  chiefly 
the  result  of  the  widening  of  Fontana's  spaces  which  results  from  the 
concentric  movement  inward  of  the  ciliary  body,  as  a  consequence 
of  which  the  outward  passage  of  vitreous  fluid  is  markedly  facilitated. 
Figs.  9  and  10,  representing  preparations  of  monkey's  eyes  fixed,  one 
with  the  ciliary  muscle  relaxed  and  the  other  with  this  muscle  con- 
tracted, illustrate  this  action.  This  effect  is  aided  by  the  contraction 


150 


PHARMACOLOGY  OF  THE  EYE 


of  the  internal  blood-vessels  of  the  eye  caused  by  eserine,  which  thus 
lessens  the  secretion  of  the  vitreous  humor  (Laqueur). 

According  to  Gronholm,  in  rabbits  this  action  on  the  vessels  is  the  only 
cause  of  the  diminution  of  pressure.  Knape,  on  the  other  hand,  found  that 
eserine,  like  atropine,  always  caused  an  active  hypersemia  of  the  rabbit's  iris  and 
no  alterations  in  the  blood-vessels  of  the  fundus.  Moreover,  in  his  experiments  on 
the  normal  eye,  which  were  carried  on  with  the  observation  of  every  precaution 
against  error,  he  never,  with  the  exception  of  very  temporary  variations  at  first, 
was  able  to  observe  any  alteration  of  the  intra-ocular  tension,  neither  diminution 
in  eserine  miosis  nor  an  increase  in  atropine  mydriasis,  observations  which  are 
explained  by  the  assumption  that  the  regulatory  mechanism  of  the  normally 
functioning  eye  prevents  such  effects.  When  this  is  disturbed,  however,  contrac- 
tion or  relaxation  of  the  iris  produces  changes  in  the  intra-ocular  tension. 

In  the  treatment  of  glaucoma,  eserine  may  consequently  serve  to 
render  iridectomy  possible,  not  only  by  spreading  out  the  iris  but 
also  by  directly  diminishing  the  pathologically  increased  tension. 


Iris  pulled  forward  and  flattened 
FIG.  10. — Monkey's  eye  after  eserine  (Heine). 

In  connection  with  the  instillation  of  %-l  per  cent,  solutions  of 
physostigmine  in  the  eye,  it  should  be  noted  that  the  greater  portion 
of  the  instilled  fluid  reaches  the  nose  and  mouth  through  the  lachrymal 
canals,  and  that  it  thus  may  cause  a  systemic  poisoning.  This  may  be 
prevented  by  closure  of  these  canals  for  a  time  by  pressing  on  them 
with  the  finger,  a  procedure  which  may  be  adopted  when  any  medicinal 
solutions  are  applied  to  the  eye. 

Other  Actions  of  Physostigmine  on  the  Autonomic  Nerve-endings. — 


MIOTICS  ACTING  IN  PERIPHERY  151 

The  same  augmentation  of  excitability  already  described  as  produced 
by  eserine  in  the  oculomotorius  mechanism  is  produced  by  it  in  all 
other  autonomic  (parasympathetic)  nerve-endings,  causing  augmen- 
tation of  the  excitability  of  the  cardiac  vagus  ( Winterberg),  of  the 
intestinal  vagus,  chorda  tympani,  and  N.  pelvicus  (Loewi  u.  Mans f  eld) , 
and  also  of  the  nerve-endings  in  the  sweat-glands. 

Consequently,  with  the  systemic  action  of  physostigmine  there  is 
increased  flow  of  the  tears  and  saliva,  increased  secretion  of  the  mucous 
and  bronchial  glands,  profuse  sweating,  increased  contraction  of  the 
muscles  of  the  bronchi,  stomach,  and  intestines,  vomiting  and  violent 
purging,  as  also  spasmodic  contractions  of  the  bladder  and  at  times  of 
the  uterus,  and  finally  a  slowing  of  the  action  of  the  heart.  All  these 
effects  may  be  overcome  by  sufficiently  large  doses  of  atropine.  Thera- 
peutically  we  make  use  only  of  its  actions  on  the  intestine  in  conditions 
of  atony,  tympanites,  etc. 

Action  on  Motor  Nerves  of  Striped  Muscles. — Further,  physostig- 
mine increases  the  excitability  not  only  of  the  above-mentioned  auto- 
nomic nerve-endings  but  also  that  of  the  nerve-endings  supplying  volun- 
tary muscles.  The  excitability  of  these  peripheral  terminal  organs 
is  so  increased  that  previously  subliminal  stimuli  become  effective.  If 
the  motor  nerve-endings  have  been  paralyzed  by  curare  to  such  a 
degree  that  even  the  very  strongest  faradic  stimulation  of  the  nerve 
produces  no  effect,  the  excitability  may  be  again  restored  by  eserine 
and  then  again  completely  paralyzed  by  large  doses  of  curare.  This 
explains  why  curarized  animals  which  are  already  suffering  from 
asphyxia  begin  to  breathe  again  after  the  injection  of  eserine  and  are 
again  able  to  move  (see  curare,  p.  11). 

Harnack  and  Witkowski,  by  investigating  the  strength  of  the  directly  applied 
induction  current  necessary  to  produce  contractions  of  the  muscles,  have  been 
able  to  show  that  the  excitability  of  curarized  frog  muscles  is  increased  by  eserine, 
and  attribute  this  result  to  an  action  on  the  contractile  substances  of  the  muscles. 
It  is  possible,  however,  that  this  effect  may  be  due  to  an  action  on  nervous  ele- 
ments lying  peripherally  to  the  point  at  which  curare  acts,  for  the  direct  faradic 
stimulation  of  curarized  animals  probably  does  not  act  directly  on  the  muscle-cells 
themselves  or  upon  these  alone,  but  also  on  the  terminal  nervous  organs  which  lie 
beyond  that  part  of  the  nerve  which,  is  paralyzed  by  curare  (Herzen,  Joteyko). 

Moreover,  the  physostigmine  produces  another  very  striking  and 
theoretically  important  effect  in  the  striped  muscles, — namely,  fibril- 
lary  or,  more  correctly,  fascicular  twitchings  which  extend  over  the 
whole  body  and  resemble  violent  shivering  from  cold.  This  effect 
must  be  due  to  an  action  on  the  nervous  terminal  organs,  for,  after 
section  of  the  nerves,  these  twitchings  continue  although  with  dimin- 
ished intensity,  but  may  no  longer  be  induced  in  the  muscles  whose 
nerves  have  been  divided  and  have  degenerated  (Magnus).  They  are 
not  inhibited  by  curare,  but  are  readily  stopped  by  small  doses  of 
atropine  (Rothberger)  and  by  lime  salts  (Loewi). 

These  phenomena  suggest  that  autonomic  nerve-endings  play  a  role 


152  PHARMACOLOGY  OF  THE  EYE 

in  producing  this  twitching  of  the  muscles,  and  that,  therefore,  besides 
spinal  motor  nerves,  not  only  sympathetic  vasomotor  nerves  but  also 
motor  autonomic  (parasympathetic)  fibres  supply  the  voluntary  mus- 
cles, which  last-mentioned  nerves  play  a  role  in  the  regulation  of  heat. 

It  also  appears  that  in  these  two  systems,  the  autonomic  or  parasympathetic 
and  the  spinal,  we  are  dealing  with  a  reciprocal  antagonism  between  eserine  and 
atropine  in  one  system  and  eserine  and  curare  in  the  other,  in  both  of  which  cases 
physostigmine  is  the  weaker  antagonist.  We  may  understand  this  by  conceiving 
that  eserine  and  atropine  exhibit  a  tendency  to  enter  into  a  reversible  chemical 
combination  with  the  same  substances  in  the  nerve-endings,  these  different 
drugs  causing  opposite  effects  on  the  functions  and  possessing  a  chemical  affinity 
for  these  substances  of  very  different  intensity,  so  that  physostigmine,  with  less 
affinity  for  these  substances,  may  be  forced  out  from  these  combinations  by  veiy 
small  quantities  of  atropine  or  curare,  both  of  which  possess  much  stronger 
affinities  to  it,  in  a  fashion  similar  to  that  in  which  oxygen  is  forced  by  carbon 
monoxide  out  of  its  combination  with  haemoglobin.  It  is,  however,  possible,  and 
in  fact  more  probable,  that,  at  any  rate  for  physostigmine  and  atropine,  in  the 
iris  the  points  at  which  the  action  is  produced  are  not  the  same. 

The  elements  in  the  iris  which  are  acted  upon  by  eserine  disappear  with  the 
degeneration  of  the  nerves,  which  follows  destruction  of  the  short  ciliary  nerves 
or  the  ciliary  ganglion,  but  there  still  remain  in  the  iris  certain  excitable  elements 
which  are  not  purely  muscular  in  their  nature  but  which  seem  to  consist  of  a 
myoneural  intermediary  substance.  This  intermediary  substance  is  not  suscep- 
tible to  the  action  of  eserine,  but  is  excited  by  pilocarpine  (see  p.  153)  so  that 
miosis  is  induced.  Atropine  overcomes  this  action  of  pilocarpine,  and  conse- 
quently in  all  probability  produces  its  effects  by  acting  on  this  intermediary 
substance  (Anderson).  With  moderate  atropinization,  therefore,  a  block  is 
formed  through  which  the  normal  stimulating  impulses  of  the  oculomotorius 
cannot  pass,  but  which  is  passed  by  these  stimuli  when  they  are  increased  by 
the  action  of  eserine.  Complete  atropinization,  however,  can  prevent  this  passage 
of  such  stimuli  to  the  contractile  substance,  and  it  is  thus  evident  that  the 
antagonism  between  atropine  and  eserine  is  not  reciprocal  in  the  strict  sense. 

Actions  on  Heart  and  Central  Nervous  System. — In  conclusion  it 
should  be  mentioned  that  eserine  also  produces  certain  stimulating1 
effects  in  the  cardiac  muscle  (Winterberg) ,  and  that  the  augmentation 
of  the  nervous  excitability  produced  by  eserine  is  not  limited  to  the 
peripheral  organs  but  manifests  itself  also  in  certain  portions  of  the 
brain  and  cord.  The  respiration  is  strengthened  and  deepened,  as  a 
result  of  an  action  on  the  peripheral  vagus  endings  in  the  lungs  (Bezold 
and  Goetz)  and  also  of  a  direct  stimulation  of  the  medullary  respira- 
tory centre  (Rothberger) .  The  motor  cortical  centres  are  also  ren- 
dered more  excitable,  an  effect  which  is  especially  marked  in  the 
presence  of  a  tendency  to  epileptic  convulsions  (Harnack  11. 
Witkowski) . 

[The  fairly  wide-spread  use  of  physostigmine  in  the  treatment 
of  tetanus  is  not  justified  by  our  knowledge  of  its  pharmacological 
actions.  On  the  contrary,  all  that  we  know  of  it  forbids  its  employ- 
ment in  such  conditions. — TR.] 

BIBLIOGRAPHY 

Anderson:    Journ.  of  Phys.,  1905,  vol.  32,  1906,  vol.  33. 

Gronholm:   Griife's  Arch.,  1900,  vol.  49,  p.  620. 

Hamer,  1863:  cited  by  Snellen  in  Grafe-Samisch's  Handbuch,  1905. 


MIOTICS  ACTING  IN  PERIPHERY  153 

Harnack  u.  Witkowski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5. 

Heine:   Griife's  Arch.  f.  Ophthal.,  1899,  vol.  49,  No.  1. 

Herzen:   Intermed.  des  Biolog.,  1898,  vol.  15. 

Joteyko:  Inst.  Solvay,  Trav.  4,  1901. 

Knape:  Arb.  Physiol.  Inst.  Helsingfors.  Festschr.,  1910,  p.  215. 

Laqueur:   Arch.   f.  Ophth.,   1877,   vol.  23,   p.   149. 

Loewi  u.  Mansfeld:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  180. 

Magnus:   Pfliiger's  Arch.,  1908,  vol.  123. 

Rothberger:   Pttiiger's  Arch.,  1901,  vol.  87. 

Waymouth  Reid:   Journal  of  Phys.,  1895,  vol.  17. 

Winterberg:   Ztschr.  f.  exp.  Path.  u.  Ther.,  1907,  vol.  4,  here  lit. 

PILOCARPINE 

.  Pilocarpine  acts  on  the  iris  and  ciliary  muscle  similarly  to  physo- 
stigmine,  causing  miosis,  spasm  of  accommodation,  and  diminution  of 
intra-ocular  tension;  but  all  these  actions  are  weaker  and  less  per- 
sistent and  are  produced  only  by  much  stronger  solutions  (4  per  cent.) 
(Jaarsma) .  A  difference  in  their  actions  which,  while  not  particularly 
important,  is  theoretically  a  fundamental  one,  is  that  pilocarpine  does 
not,  like  eserine,  increase  the  excitability  of  the  nerve-endings,  but 
actually  directly  stimulates  them.  The  miosis  produced  by  it  occurs 
even  after  abolition  of  the  central  innervation  by  post-ganglionic  sec- 
tion of  the  oculomotorius  and  in  spite  of  a  persisting  antagonistic 
action  of  the  sympathetic.  With  the  passing  off  of  its  visible  effects, 
the  latent  increased  excitability  does  not  remain,  as  is  the  case  with 
physostigmine,  but  in  place  of  it  there  is  a  paresis  of  the  oculomotorius 
nerve-endings,  the  pupils  becoming  wide  or  normal  (Harnack  u. 
Meyer},  the  accommodation  remaining  impaired,  and  the  near  point 
being  rendered  more  distant  (Falchi).  The  other  actions  of  pilo- 
carpine on  the  autonomic  terminal  nervous  organs  are  also  to  be 
considered  as  due  to  a  direct  excitation. 

In  respect  to  their  actions  on  the  eye  and  on  most  of  the  other  autonomi- 
cally  innervated  organs,  nicotine,  muscarine  (Schultz),  and  choline  (F.  Milller) 
resemble  pilocarpine,  as  does  arecoline,  a  base  obtained  from  the  betel-nut.  The 
hydrobromate  of  this  base,  when  instilled  into  the  eye  in  1  per  cent,  solution, 
produces  miosis  and  a  passing  spasm  of  the  accommodation,  which  is  followed 
by  slight  mydriasis  (Marme,  Lavagna,  Frohner). 


Falchi :   Giorn.  della  R.  ace.  di  med.  di  Torino,  1885. 

Frohner:   Monatsh.  f.  prakt.  Tierheilkunde,  1894. 

Harnack  u.  Meyer:   Arch.  f.  exp.  Path.  u.  Pharm.,  1880,  vol.  12. 

Jaarsma:  Diss.  Leiden.,  1880. 

Lavagna:    Therap.  Monatsh.,  1895,  p.  365. 

'Marine :    Gottinger   Nachrichten,    1889. 

Muller,  F.:   Pfliiger's  Arch.,  1910,  vol.  134,  p.  289. 

Schultz:   Arch.  f.  Physiol.,  1898. 

ATROPINE 

Atropine  and  its  congeners  produce  the  opposite — i.e.,  a  paralytic — 
effect  on  the  autonomically  innervated  organs.  This  alkaloid,  with 
the  empiric  formula  C17H23N03,  occurs  in  all  the  solanaceas. 


154  PHARMACOLOGY  OF  THE  EYE 

In  its  constitution  it  is  a  basic  ester,  which  may  be  decomposed  by  alkalies 
or  acids  into  a  basic  alcohol,  tropine,  and  an  aromatic  acid,  tropaic  acid. 


H,0  =  C8H15NO  +  COOH.CSHSOH. 
Atropine.  Tropine.  Tropaic  acid. 

According   to   Willstatter,    its   constitution   may   be   represented   as    follows : 

H  H2 

H2C C 

CH2OH 

>NCH3    >CHO-CO-C-H 


Tropaic  acid. 

For  two  reasons  this  formula  possesses  for  us  considerable  interest.  The 
basic  portion,  tropine,  is  closely  related  to  ecgonine  (see  p.  121)  ;  the  basic  portion 
of  cocaine,  which  is  also  an  ester  and  which  in  many  particulars  exerts  actions 
similar  to  those  of  atropine.  As  the  formula  shows,  tropaic  acid  contains 
an  asymmetrical  carbon  atom,  and  occurs  in  three  modifications,  a  laevorotatory, 
a  dextrorotatory,  and  a  racemic  inactive  one,  and  forms  correspondingly  different 
tropeins.  Ordinary  atropine  is  optically  inactive,  being  formed  of  a  mixture 
of  laevorotatory  and  dextrorotatory  bases,  of  which  the  former  is  identical  with 
the  natural  1-hyoscyamine.  This  1-hyoscyamine  has  twice  as  strong  an  action 
on  the  autonomic  nerve-endings  as  has  atropine,  a  fact  which  is  accounted  for 
by  the  further  fact  that  r-hyoscyamine  is  almost  without  action  on  these  organs 
(Cushny).  The  closely  related  alkaloids  1-  and  r-scopolamine  exhibit  the  same 
remarkable  difference  in  their  physiological  actions  (Cushny),  and  similar 
differences  are  noted  in  connection  with  other  drugs,  as,  for  example,  in  1-  and 
r-epinephrin.  The  reason  of  this  different  physiological  behavior  of  optical 
isomeres  is  unknown. 

MYDRIATIC  ACTION.  —  If  a  drop  of  a  1  per  cent,  solution  of  atropine 
be  instilled  into  the  conjunctiva!  sac,  after  about  15  minutes  the  pupils 
commence  to  dilate,  and  about  the  same  time  the  near  point  moves  out, 
which  action  continues  until  the  accommodation  is  completely 
paralyzed.  Both  of  these  actions  are  due  to  paralysis  of  the  autonomic 
oculomotorius  nerve-endings  in  the  sphincter  of  the  iris  and  in  the 
ciliary  muscle,  for,  when  the  oculomotorius  is  stimulated  inside  the 
skull  or  the  short  ciliary  nerves  are  stimulated  in  the  orbit,  no  effect 
is  produced  on  the  iris  of  an  atropinized  eye  although  the  sphincter 
muscle  still  reacts  well  to  stimulation  (Schultz}. 

In  so  far  as  paralysis  of  the  sphincter  in  all  probability  increases 
the  tone  of  the  antagonistic  dilator,  atropine  also  causes  an  increase 
of  the  tone  or  of  the  excitability  of  the  sympathetically  innervated 
dilator.  However,  this  action  is  neither  very  apparent  nor  important, 
for  after  even  the  strongest  atropinization  it  is  always  possible  to  dilate 
the  widened  pupil  still  farther  by  central  electrical  or  peripheral 
pharmacological  stimulation  of  the  sympathetic  nerves.  When  the 
normal  central  inhibition  of  the  oculomotorius  is  abolished,  as  is  the 
case  in  sleep  (Rudolph}  or  in  chloral  narcosis  (Levinstein,  Ulrich], 


ATROPINE  155 

the  pupil  already  dilated  by  atropine  dilates  still  further.  Even  this, 
however,  does  not  indicate  that  atropine  directly  stimulates  the  sympa- 
thetic nerve-endings,  but  only  that  it  depresses  the  cranial  autonomic 
(parasympathetic)  oculomotorius  endings. 

Duration  of  the  Action. — The  effect  of  atropine  in  the  eye  persists 
for  a  number  of  days,  the  paralysis  of  accommodation  disappearing 
completely  only  at  the  end  of  2-3  days,  and  the  mydriasis  only  after 
8-10  days.  In  old  people  the  effect  on  the  iris  is  slight,  while  in 
presbyopia  it  is  almost  nil. 

OTHER  ACTIONS  IN  THE  EYE. — The  deceptive  micropsia  produced 
by  atropine  is  explained  in  an  analogous  fashion  to  the  macropsia  pro- 
duced by  eserine.  As  the  wide  non-reacting  pupil  permits  the  unhin- 
dered entrance  of  bright  light,  dazzling  and  photophobia  result. 
Through  the  retraction  of  the  iris  the  spaces  of  Fontana  are  so  distorted 
that  the  exit  of  fluid  from  the  chamber  of  the  eye  is  hindered,  and 
consequently  the  intra-ocular  tension  is  increased,  so  that  in  patients 
with  a  disposition  to  glaucoma  an  acute  attack  may  be  precipitated 
(sec  p.  150). 

Atropine  exerts  no  action  upon  the  oculomotorius  nerve-endings  in  the 
iris  of  birds  and  reptiles  in  which  the  iris  is  composed  of  striped  muscle-fibres. 
These  nerve-endings,  however,  are  paralyzed  by  curare,  but  not  by  numerous 
quaternary  ammonium  bases  which  in  other  particulars  act  like  curare,  but 
on  the  contrary  they  are  strongly  stimulated  by  them.  There  is,  therefore,  no 
essential  similarity  in  the  behavior  of  the  striped  muscle  of  the  bird's  iris  and 
that  of  the  other  striped  muscles  (U.  Meyer). 

USES  IN  OPHTHALMOLOGY. — Atropinization  of  the  eye  by  abolishing 
the  accommodation  renders  possible  the  exact  determination  of  the 
refraction,  and,  by  widening  the  pupils,  facilitates  ophthalmoscopic 
examination  of  the  lens  and  of  the  fundus  and  the  performance  of 
operations  on  the  lens,  etc.  Moreover,  the  complete  quieting  of  the 
internal  muscles  of  the  eye  produces  most  favorable  effects  in  painful 
spasm  of  the  accommodation  and  in  all  inflammatory  conditions  such 
as  iritis,  etc.  This  latter  action  is  augmented  by  a  slight  anesthetic 
action  on  the  sensory  nerve-endings  of  the  cornea  and  iris.  For  these 
various  reasons,  atropine  has  become  one  of  the  drugs  most  frequently 
used  in  ophthalmology.  It  should,  however,  be  noted  that  the  repeated 
instillation  of  atropine  into  the  eye  is  followed  at  times  by  a  conjuncti- 
vitis and  more  rarely  by  oedema  of  the  lids  (Uhthoff).  The  cause  of 
this  harmful  action  is  not  known. 

SYSTEMIC  ACTIONS. — The  peripheral  action  of  atropine  is  exerted 
on  all  parasympathetic  terminal  nervous  organs,  and  consequently, 
generally  speaking,  it  depresses  the  motor  activity  and  the  tone  of 
smooth  muscles  as  well  as  the  secretory  activity  of  glands.  Not  only  do 
the  mouth  and  skin  become  dry  as  a  result  of  the  diminution  of  the 
secretions,  but  the  secretion  of  the  gastric  and  intestinal  glands  also 
is  diminished.  In  the  heart  the  inhibitory  vagal  nerve-endings  are 
paralyzed,  so  that  the  heart  beats  very  rapidly  and  the  blood-pressure 


156  PHARMACOLOGY  OF  THE  EYE 

rises,  while  the  skin  becomes  red  as  a  result  of  the  marked  dilatation 
of  the  small  cutaneous  vessels  and  the  body  temperature  rises  (Morat 
et  Doyon). 

ACUTE  POISONING. — From  these  various  actions  arise  the  character- 
istic symptoms  of  acute  atropine  poisoning,  such  as  is  not  infrequently 
observed  particularly  in  children  who  have  eaten  belladonna  berries. 
These  symptoms  are  a  scarlet-red,  dry,  hot  skin,  very  rapid  breathing 
and  pulse,  and  dilated  pupils,  with  which  are  associated  active  excite- 
ment, with  delirium,  laughing  or  crying,  marked  motor  activity  or  even 
convulsions.  As  a  result  of  the  paralysis  of  part  of  the  swallowing 
muscles,  there  is  an  inability  to  swallow.  Finally  central  paralysis 
develops,  causing  stupor,  an  irresistible  tendency  to  sleep,  and  pro- 
found coma  that  may  pass  over  into  death. 

Even  a  few  milligrammes  of  atropine  cause  in  man  very  pro- 
nounced and  often  violent  symptoms  of  poisoning,  but  without  danger- 
ous results,  which  latter  occur  only  after  decidedly  larger  doses.  The 
lethal  dose  for  adults  is  stated  to  be  0.1  gm.,  and  this  is  probably 
too  small,  but  in  children  0.01  gm.  may  cause  death. 

In  addition  to  the  chemical  and  particularly  the  pharmacological  reactions 
of  atropine,  the  blue  fluorescence  of  the  urine  caused  by  the  glucoside  scopoletin, 
which  is  present  in  belladonna,  as  well  as  in  the  Scopola  japonica,  may  be  of 
assistance  in  recognizing  and  proving  poisoning  produced  by  these  plants 
(A.  Paltauf). 

TREATMENT. — The  most  essential  point  in  the  treatment  of  atropine 
poisoning  is  the  thorough  washing  out  of  the  stomach.  If  a  condition 
of  marked  excitement  be  present,  morphine  should  be  administered.  In 
the  dangerous  comatose  stage  the  various  cerebral  stimulants,  caffeine, 
strychnine,  and  camphor,  may  be  administered,  and  it  is  probable  that 
free  infusion  of  warm  Ringer's  solution  or  of  normal  saline  solution 
may  be  of  value  by  helping  to  dilute  and  to  eliminate  the  poison.  As 
the  bladder  is  usually  paralyzed,  it  must  be  emptied  by  catheter. 

Chronic  poisoning  may  result  from  the  long-continued  medicinal  use  of 
atropine  or  the  related  alkaloids,  and  is  characterized  by.  loss  of  appetite  and 
emaciation  (v.'Anrep,  Marandon  de  Montyel).  It  is  possible  that  such  poison- 
ing is  chiefly  due  to  a  persistent  or  at  least  frequently  repeated  paralysis  of  the 
glandular  secretions. 

Certain  herbivorous  animals,  particularly  goats,  sheep,  and  rabbits,  show 
a  very  remarkable  resistance  to  atropine.  With  rabbits  this  is  due  to  the  fact 
that  their  blood  detoxicates  atropine  ( Fleischmann ) ,  as  does  also  the  liver 
(Cloetta).  Horses  and  cattle  are  much  more  susceptible,  but  dogs  of  medium 
size  support  doses  of  as  much  as  1.0  gm.  or  more,  while  cats  die  after  receiving 
a  few  centigrammes. 

THERAPEUTIC  USES. — In  addition  to  its  use  in  ophthalmology, 
atropine  may  be  employed  for  its  therapeutic  effects  in  all  those 
conditions  in  which  its  actions  upon  the  terminal  organs  of  the  auto- 
nomic  (parasympathetic)  nervous  system  are  indicated.  For  example, 
for  the  purpose  of  inhibiting  the  secretion  of  various  glands,  in  pro- 
fuse sweating,  salivation,  or  lachrymation,  in  spasmodic  conditions  of 


ATROPINE  SUBSTITUTES  157 

the  organs  containing  smooth  muscles,  such  as  the  bronchi,  stomach, 
intestines,  gall-bladder,  urinary  bladder,  uterus,  etc.,  or  in  conditions 
in  which  there  is  an  abnormal  stimulation  of  the  cardiac  vagus.  It  may 
also  be  employed  to  stimulate  the  central  nervous  system,  particularly 
the  respiratory  centre,  as  in  morphine  poisoning  (E.  Reichert). 

Preparations. — In  addition  to  atropine  sulpate  (0.0005-0.001  gm.  (!)  per 
dose,  0.003  gm.  (  ! )  per  diem ) ,  various  galenic  preparations  of  belladonna,  hyo- 
scyamus,  etc.,  are  used  in  medicine.  The  extracts  contain  1-1%  per  cent,  alka- 
loids, of  which,  however  1-hyoscyamine  makes  up  the  greater  portion  and 
atropine  the  lesser.  In  hyoscyamus,  in  addition  to  hyoscyamine  there  are  small 
amounts  of  hyoscine  or  scopolamine,  which  accounts  for  its  more  pronounced 
sedative  action. 

SUBSTITUTES  FOR  ATROPINE 

HOMATROPINE,  a  synthetically  prepared  ester  of  tropine  with  man- 
delic  acid, 

/OH 

CeHjCH^ 

KX)OH, 

has  qualitatively  the  same  pharmacological  action  as  atropine  but  is 
much,  weaker.  It  is  widely  employed  as  a  mydriatic,  causing  a  more 
prompt  but  less  lasting  mydriasis  than  atropine. 

SCOPOLAMINE,  or  HYOSCINE,  has  also  been  used  as  a  mydriatic  in 
Yio-Ys  per  cent,  solutions,  but  is  more  usually  employed  as  a  narcotic 
(see  p.  27).  It  is  a  tropaic  acid  ester  of  scopoline. 

Eumydrine. — By  the  addition  of  a  methyl  group  the  tertiary 
atropine  may  be  transformed  into  the  quaternary  base,  methyl  atropi- 
num,  the  nitrate  of  which  has  been  introduced  as  a  mydriatic  under 
the  name  eumydrine.  In  it  the  general  actions  on  the  central  nervous 
system  have  been  markedly  weakened  \?hile  the  local  effects  in  the  eye 
are  retained  (Lindenmeyer) . 

Euphthalmine,  C17H2BNO3,  the  hydrochloride  of  the  mandelic  acid 
ester  of  methylvinyldiacetone-alkamine,  is  a  synthetically  prepared 
alkaloid,  which,  like  atropine,  paralyzes  the  oculomotorius  endings, 
but  only  in  much  stronger  solutions  (5-10  per  cent.)  (T rentier}. 

BIBLIOGRAPHY 

j 

v.  Anrep:  Pfliiger's  Arch.,  1880,  vol.  21. 

Cushny:   Journ.  of  Phys.,  1903,  vol.  30;  1905,  vol.  32.  / 

Gadamer:  Arch,  d.  Pharm.,  1901,  vol.  239,  p.  294. 

Levinstein:   Berl.  klin.  W.,  1876,  No.  27. 

Lindenmeyer:    Berl.    klin.    Woch.,    1903,    No.    47. 

Marandon  de.Montyel:   Bull,  de  Ther.,  Feb.  25,  1894,  vol.  126. 

Meyer,  H.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  vol.  32. 

Morat  et  Doyon:    Compt.  rend.  d.  1.   Soc.   Biol.,   1892. 

Paltauf,  A.:     Wien.  klin.  Woch.,  1888,  No.  5. 

Reichert,  E.:  The  Therap.  Monthly,  Philad.,  1901. 

Rudolph:  Zentralbl.  f.  klin.  Med./1892,  No.  40,  p.  833. 

Schultz:  Engelmann's  Arch.,  1898,  lit.  here. 

Treutler:  Klin.  Mon.  f.  Augenheilk.,  1897,  p.  285. 

Uhthoff,  Grafe-Samisch's  Handb.,  1901,  vol.  11,  chap.  22,  lit.  here. 

Ulrich:   Arch.  f.  Ophth.,  1887,  vol.  33,  p.  2. 

Waymouth  Reid:    ' Journ.  of  Phys.,  1895,  vol.  17. 


158  PHARMACOLOGY  OF  THE  EYE 

COCAINE 

The  vasoconstrictors  of  the  eye  and  the  nerves  supplying  the 
radial  muscles  of  the  iris  and  the  smooth  muscles  of  the  lids  (Miiller's 
muscle)  are  derived  from  the  sympathetic  system.  Their  nerve- 
endings  are  all  stimulated  if  a  solution  of  cocaine  be  instilled  into  the 
conjunctival  sac,  but,  as  cocaine,  when  thus  applied,  does  not  reach  the 
retinal  vessels,  constriction  has  been  observed  only  occasionally  in  cases 
of  general  poisoning  by  cocaine  (Uhtkoff).  On  the  other  hand,  the 
vessels  of  the  conjunctiva  and  the  iris  are  strongly  constricted  and 
the  pupils  dilated  while  the  palpebral  opening  is  somewhat  widened. 
The  mydriasis  is  not  maximal  and  the  iris  still  reacts  to  light,  although 
to  a  somewhat  limited  extent,  indicating  that  the  function  of  the 
oculomotorius  nerve-endings  has  not  been  abolished.  A  further  proof 
that  this  is  so  is  furnished  by  the  positive  effect  in  the  cocainized  eye  of 
stimulating  this  nerve  intracranially.  Accommodation  also  remains 
almost  completely  normal.  Only  after  long-continued  bathing  of  the 
eye  with  a  strong  (5  per  cent.)  solution  of  cocaine  is  the  excitability 
of  the  oculomotorius  nerve-endings  abolished. 

If  the  sympathetic  is  divided  peripherally  to  the  superior  cervical  ganglion, 
for  a  time  cocaine  still  dilates  the  contracted  pupil,  but  if  after  a  time  degenera- 
tion of  the  sympathetic  nerve-endings  has  occurred,  cocaine  no  longer  produces 
any  noticeable  effects;  consequently,  it  may  be  concluded  that  its  action  is 
confined  to  the  nervous  element  only  (ticfvultz). 

As  cocaine  paralyzes  the  sensory  trigeminal  nerve-endings  of  the  cornea 
and  conjunctiva,  it  might  be  thought  that  the  mydriasis  produced  by  it  is 
due  to  the  abolition  of  sensory  stimuli  and  to  a  failure  of  the  reflex  contractions 
of  the  iris  dependent  thereon.  This  explanation,  however,  is  shown  to  be  wrong 
by  the  fact  that  other  local  anaesthetics,  such  as  holocaine,  /3-eucaine,  etc.,  do 
not  cause  any  mydriasis. 

EFFECTS  ON  INTRA-OCULAR  TENSION. — As  a  rule,  cocaine  diminishes 
intra-ocular  tension,  probably  on  account  of  its  power  of  constricting 
the  vessels  of  the  ciliary  body  of  the  iris,  from  which  the  fluid  of 
the  aqueous  chamber  is  derived.  However,  the  retraction  of  the  iris  by 
narrowing  the  canals  of  Schlemm  tends  to  oppose  this  diminution  of 
the  intra-ocular  tension  and  may,  in  fact,  particularly  in  patients  suf- 
fering from  glaucoma,  at  times  cause  an  acute  attack  of  glaucoma 
(Uhthoff). 

USES  IN  THE  EYE. — Since  its  introduction  by  Koller,  cocaine  has 
come  to  be  a  drug  which  could  hardly  be  spared  in  ophthalmology, 
for  it  very  quickly  produces  a  mydriasis  lasting  only  for  a  few  hours, 
anajsthesia  of  the  cornea  and  conjunctiva,  and  anaemia  of  the  ocular 
tissues.  Its  value  here  is  somewhat  lessened  by  its  liability  to  damage 
the  cornea,  diffuse  opacities  of  the  cornea  being  quite  readily  caused 
and  the  healing  of  wounds  of  the  cornea  being  retarded  by  it. 

That  the  abolition  of  the  function  of  the  sensory  trigeminal  nerve-endings 
may  be  a  direct  cause  of  trophic  disturbances,  if  the  blood-vessels  of  the  eye  be 
constricted,  is  demonstrated  by  the  fact  that  a  neuroparalytic  keratitis  may  result 


EPINEPHRIN  159 

from  the  simple  removal  of  the  Gasserian  ganglion,  including  the  vasodilator 
nerves  of  the  anterior  eye  which  run  in  the  ramus  ophthalmicus,  but  if  at  the 
same  time  the  cervical  sympathetic  and,  with  it,  tne  vasoconstrictors  of  the  eye 
are  divided,  no  changes  occur  in  the  cornea  (Spallita).  In  man,  however,  because 
of  the  consensual  closure  of  the  lid,  keratitis  does  not  usually  occur  after  one- 
sided extirpation  of  the  Gasserian  ganglion  (Krause). 

Ephedrine  and  pseudo-epkcdrine  (Giinsburg},  alkaloids  prepared 
from, Ephedra  vulgaris  and  (3-tetrahydronaphthylamine  (Stern),  act 
on  the  dilators  of  the  iris  and  on  Muller's  muscle  similarly  to  cocaine. 

BIBLIOGRAPHY 

Gunsburg:  Virchow's  Arch.,  1891,  vol.  124,  p.  75. 
Roller:   Wien.  med.  Woch.,  1884,  No.  43,  44. 
Krause:   Miinchn.  med.  Woch.,   1895. 
Schultz:   Dubois'  Arch.  f.  Physiol.,   1898. 
Spallita:   Arch,  di  Ottalm.,  vol.  2,  No.  1,  1884. 
Stern:  Virchow's  Arch.,  1889,  vols.  115  and  117. 
Uhthoff :   loc.  cit. 

EPINEPHRIN 

Epinephrin  and  the  related  synthetic  compounds  (Loewi  u.  Meyer} 
act  upon  those  elements  of  the  eye  which  are  innervated  from  the 
sympathetic  system  in  the  same  fashion  as  does  very  strong  stimulation 
of  the  sympathetic  nerve  (Wessely).  Fractions  of  a  milligramme 
injected  intravenously  cause  a  very  pronounced  mydriasis,  which, 
however,  lasts  but  a  few  seconds,  and  may  even  cause  a  momentary 
increase  in  the  dilation  of  a  pupil  already  maximally  dilated  by 
atropine  (Lewandoivsky) .  At  the  same  time  the  eyebalHs  protruded 
and  the  vessels  of  the  eye  are  constricted.  When  instilled  into  the 
conjunctival  sac  in  a  strength  of  1 : 1000  or  even  of  1 : 10,000,  epi- 
nephrin  powerfully  constricts  the  conjunctival  vessels,  but,  as  a  rule, 
in  man  causes  no  noticeable  mydriasis,  and  also  none  in  dogs  and  cats, 
but  does  so  in  rabbits  and  particularly  in  frogs  (W.  H.  Schultz, 
Meltzer  u.  Auer).  If,  however,  the  sympathetic  nerve-endings  of  the 
iris  are  themselves  abnormally  excitable  or  are  less  inhibited  by  the 
antagonistic  autonomic  oculomotorius  mechanism  than  normally,  the 
instillation  of  epinephrin  causes  a  distinct  or  pronounced  mydriasis. 
This  is  the  case  in  man  in  many  cases  of  Basedow's  disease,  in  which 
there  is  an  increased  excitability  of  the  sympathetic  innervation,  and 
also  in  cases  with  insufficiency  of  the  pancreas,  such  as  severe  diabetes 
in  man,  or  in  dogs  and  cats  in  which  the  pancreas  has  been  extirpated. 
This  pupillary  reaction  to  epinephrin  may  consequently  in  certain 
cases  have  some  diagnostic  significance  (Loewi). 

The  terminal  organs  of  the  sympathetic  nerve  are  also  more  excitable  if 
they  have  been  separated  from  their  centre,  the  superior  cervical  ganglion,  and 
consequently  in  such  case  the  conjunctival  instillation,  which  is  ordinarily 
without  effect,  or  the  subcutaneous  injection  of  epinephrin  may  cause  in  rabbits 
a  pronounced  and  rather  lasting  mydriasis  (Meltzer  and  Auer). 

The  susceptibility  of  the  entire  sympathetic  motor  mechanism  to  epinephrin 
may  be  enormously  increased  by  the  administration  of  cocaine.  Doses  of  cocaine, 


160  PHARMACOLOGY  OF  THE  EYE 

which  by  themselves  produce  no  marked  influence  on  the  iris  of  the  cat  or  dog, 
eo  alter  the  physiological  condition  of  this  organ  that  the  instillation  of 
epinephrin  causes  a  pronounced  mydriasis.  This  synergistic  effect  is  still  more 
clearly  shown  in  connection  with  the  action  of  these  two  drugs  on  the  sympathetic 
innervation  of  the  intestine  and  bladder  and  on  the  vasoconstrictors.  It  is  conse- 
quently very  probable  that  those  actions  of  cocaine,  which  we  call  stimulation  of 
the  sympathetic  nerve-endings,  are  essentially  due  to  a  specific  sensitization  of 
the  motor  sympathetic  nerve-endings  for  the  epinephrin,  which  is  always  present 
in  the  blood,  although  normally  in  subliminal  amounts  (Frohlich  u.  Loewi}. 

Its  local  vasoconstricting  action  on  the  conjunctiva!  vessels  and 
also,  when  injected  subconjunctivally,  on  the  vessels  of  the  iris  and 
ciliary  body  is  very  useful  in  the  practice  of  ophthalmology,  particu- 
larly when  it  is  used  in  combination  with  cocaine. 

BIBLIOGRAPHY 

Frohlich  u.  Loewi:  Arch.  f.  Exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  159. 

Lewandowsky:  Zentralbl.  f.  Physiol.,  1899,  vol.  12. 

Loewi:  Wien.  klin.  Woch.,  1907,  No.  25. 

Loewi :  Arch,  f .  exp.  Path.  u.  Pharm.,   1908,  vol.  59. 

Loewi  u.  Meyer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  53. 

Meltzer  u.  Auer:   Am.  Journ.  of  Physiol.,  1904,  vol.  11. 

Schultz,  W.  H. :  Proc.  Soc.  for  Exp.  Biol.  and  Med.,  New  York,  1908,  vol.  6,  p.  23. 

Wessely;  Ber.  d.  Ophthalm.  Ges.,  Heidelberg,  1900. 

ASTRINGENT  AND  CORROSIVE  SUBSTANCES,  or  those  which  cause  in- 
flammation, produce  the  same  changes  in  the  outer  portions  of  the 
eye,  the  cornea  and  conjunctiva,  as  in  other  mucous  membranes ;  con- 
sequently, for  their  actions  on  the  eye  the  reader  may  be  referred 
to  the  chapter  on  the  pharmacology  of  inflammation. 

ANTISEPTICS. — The  same  holds  true  also  for  the  antiseptics,  of 
which  the  mild  insoluble  mercury  preparations,  the  yellow  oxide  and 
the  white  precipitate,  in  the  form  of  ointments,  and  calomel,  in  its  most 
finely  powdered  form,  as  a  dusting  powder,  are  frequently  employed 
in  the  practice  of  ophthalmology. 

ABRIN 

In  this  section  it  seems  proper  to  discuss  in  part  the  action  of 
abrin,  a  toxin,. probably  albuminoid  in  nature,  which  is  obtained  from 
the  seeds  of  Arus  precatorius,  or  jequirity  (8.  Martin,  Osborne). 
Mere  traces  of  this  substance  applied  to  the  conjunctiva  cause  an  acute, 
rapidly  progressing  conjunctivitis,  with  emigration  of  leucocytes  and 
pronounced  serous  infiltration,  effects  which  at  times  appear  to  be  of 
value  in  the  treatment  of  sluggish  trachoma,  and  particularly  as  a 
means  of  causing  the  absorption  of  trachomatous  opacities  of  the 
cornea.  As  is  the  case  with  many  toxins  of  a  proteid  nature,  an  anti- 
toxin— antiabrin — may  under  the  influence  of  abrin  be  produced  in 
the  organism  (.Ekrlich),  and  Romer  states  that  it  is  possible  to  mod- 
erate the  intensity  of  a  too  violent  abrin  action  in  the  eye  by  the  use 
of  this  antitoxin. 


MIOTICS  ACTING  IN  PERIPHERY  161 

DIONIN  is  another  drug  causing  pronounced  conjunctival  chemosis 
and  oedema  of  the  lids,  which  consequently  may  be  used  in  the  same 
way  and  for  the  same  indications  as  abrin.  It  is  the  synthetically 
prepared  hydrochloride  of  ethyl  morphine. 

PERONIN,  the  hydrochloride  of  benzyl  morphine,  may  also  be  used 
for  similar  purposes  (Uhthoff). 

BIBLIOGRAPHY 

Ehrlich:  Deutsche  med.  Woch.,  1891.  No.  44. 

Martin,  S.,  and  Wolfenden:  Proc.  Roy.  Soc.,  London,  1889,  vol.  46. 
Osborne,  Mendel  and  Harris:  Am.  Journ.  of  Physiol.,  1905,  vol.  14. 
Romer:  Grafe'a  Arch.  f.  Ophth.,  1901,  vol.  52,  p.  72. 


CHAPTER  VI 
PHARMACOLOGY  OF  THE  DIGESTION 

i.  CHEMISTRY  OF  THE  DIGESTION 

PHARMACOLOGY  OF  THE  DIGESTIVE  GLANDS 

SALIVARY  SECRETION 

INNERVATION. — The  chemical  transformation  of  the  food  starts 
in  the  mouth  under  the  influence  of  the  secretions  of  the  salivary 
glands,  particularly  the  parotid,  submaxillary,  and  sublingual  glands, 
which  receive  their  secretory  innervation  on  the  one  hand  from  the 
superior  cervical  ganglion  of  the  sympathetic  and  on  the  other  from 


Kfaaa&r 


FIG.  11. — Innervation  of  salivary  glands.     Red,  sympathetic  nerves;  blue,  autonomic  nerves. 

cranial  autonomic  nerves.  The  autonomic  fibres  for  the  parotid  gland 
pass  from  the  auriculotemporal  branch  of  the  fifth  nerve  through 
Jacobson's  nerve  into  the  glossopharyngeal,  and  those  for  the  sub- 
maxillary  and  sublingual  glands  from  the  facial  nerve  through  the 
chorda  tympani  of  the  lingual  nerve.  Both  types  of  nerves  also  con- 
tain vasomotor  fibres  for  these  glands,  those  in  the  sympathetic  being 
vasoconstrictor  while  those  in  the  autonomic  nerves  are  vasodilator. 

162 


SALIVARY  SECRETION  163 

These  nerves  are,  therefore,  in  this  respect  antagonistic  to  each  other. 
The  secretory  fibres  are  also  in  a  sense  antagonistic,  inasmuch  as  their 
excitation  produces  in  the  glands  electric  changes  of  opposite  character 
(Bayliss  and  Bradford),  and,  while  in  both  cases  a  secretion  of  saliva 
results,  that  resulting  from  the  stimulation  of  the  sympathetic  nerves 
is  scanty  and  viscid  *  while  that  following  stimulation  of  the  chorda 
is  abundant  and  thin. 

EEFLEX  EXCITATION. — The  salivary  secretion  may  be  excited  re- 
flexly  from  the  cerebral  cortex  as  a  result  of  stimulation  of  the  appetite, 
a  fact  which  accounts  for  the  common  expression  ' '  My  mouth  waters. ' ' 
It  can,  however,  also  be  induced  by  disgust  or  nausea,  for  stimulation 
of  the  vomiting  centre  (p.  177)  also  affects  the  centres  controlling  the 
salivary  secretion.  This  secretion  may  also  be  induced  by  taste,  smell, 
and  other  sensory  stimuli  acting  upon  centres  which  lie  in  the  subcor- 
tical  regions  and  in  the  medulla.  Of  these  the  mechanical  stimulus 
resulting  from  the  act  of  chewing,  which  causes  an  abundant  secretion, 
is  especially  important. 

The  parotid  gland  is  much  more  developed  in  herbivorous  animals,  which, 
as  a  rule,  chew  their  food  for  a  longer  time  and  more  thoroughly,  than  in  the 
carnivora,  who,  as  a  rule,  bolt  their  food,  or  in  those  animals  which  live  in  the 
water.  In  man  the  average  amount  of  saliva  which  is  secreted  is  very  consider- 
able, amounting  under  the  influence  of  chewing  to  as  much  as  500-700  gm. 
in  an  hour,  and,  as  the  movements  of  talking  produce  a  similar  effect,  in  24 
hours  as  much  as  1-2  kilograms  may  be  secreted  ( Tuczek ) .  In  the  horse  and 
ox  the  amount  secreted  in  24  hours  may  exceed  40  kilograms. 

CHEMICAL,  STIMULI,  especially  acids,  bitters,  and  pungent  sub- 
stances, such  as  mustard,  by  their  action  on  the  mucous  membrane 
of  the  mouth,  reflexly  stimulate  all  these  glands,  but  especially  the 
submaxillary. 

DIRECT  STIMULATION 

Quantitatively  the  salivary  secretion  is  directly  influenced  by : 

1.  The  composition  of  the  blood, — i.e.,  the  water  content  of  the 
blood  and  the  tissues.     If  this  is  very  low,  as  after  profuse  sweating 
or  diarrhrea,  the  secretion  of  saliva  stops. 

Otherwise  the  salivary  secretion  is,  within  wide  limits,  independent  both 
of  the  blood  flow  through  the  glands  and  of  the  chemical  constituents  of  the 
blood,  it  being  little  influenced  even  by  such  substances  as  the  iodides  and 
bromides  which  are  excreted  in  it.  The  salts  of  polybasic  acids  and  sugar  are 
not  excreted  in  the  saliva,  and  metal  oxides  are  excreted  only  in  the  form  of  their 
halogen  salts  (Cl.  Bernard).  Herein  is  seen  a  fundamental  difference  in  the 
behavior  of  the  true  glands  from  that  of  the  kidneys. 

2.  Substances  which  excite  the  extra-  or  the  intra-glandular  nervous 
mechanism.     The  cranial  autonomic  organs  are  stimulated  by  these 
drugs,  which  in  general  are  autonomic  stimulants,  pilocarpine,  physo- 

*  In  the  cat  alone  the  sympathetic  saliva  is  poorer  in  ash  than  the  chorda 
saliva  (Langley). 


164  PHARMACOLOGY  OF  THE  DIGESTION 

stigmine,  muscarine,  choline,  acting  on  the  nerve-endings  while  nicotine 
stimulates  the  cells  of  the  ganglia. 


Choline,  (CHS)SNOH  CoH^O,  is  a  basic  substance  which  is  widely  dis- 
tributed throughout  the  body  (Fiirth  u.  Schwarz,  Schivarz  u.  Lederer,  Kino- 
shita)  and  which  forms  a  part  of  the  complicated  molecule  of  lecithin.  It  is 
not  improbable  that  this  substance  is  of  considerable  importance  for  the  main- 
tenance of  the  normal  tone  of  the  autonomic  ganglia  and  nervous  organs,  acting 
upon  them  perhaps  much  as  does  epinephrin  on  the  corresponding  sympathetic 
nervous  organs. 

The  power  of  TOBACCO,  especially  when  chewed  to  increase  the  secre- 
tion of  saliva,  is  a  matter  of  common  knowledge.  Profuse  salivation 
is  often  a  disturbing  side-effect  of  PILOCABPINE  when  this  drug  is 
employed  for  other  purposes,  but  small  doses  (up  to  about  0.04  gin. 
per  diem)  are  occasionally  useful  in  cases  of  suppression  of  the 
salivary  secretion  from  nervous  or  other  cause,  in  which  the  taking 
of  food  has  consequently  been  rendered  difficult. 

MERCURY  SALTS  may  also  cause  a  profuse  flow  of  saliva,  a  very 
disturbing  and  undesirable  and  by  no  means  infrequent  occurrence 
during  mercurial  treatment,  which  is  due  to  an  action  on  the  autonomic 
innervation,  but  whether  centrally  or  peripherally  is  not  known. 

INHIBITION 

All  these  autonomic  stimulations  of  the  secretion  of  saliva  may  be 
completely  inhibited  by  ATROPINE  and  its  congeners,  although  the 
vessels  in  the  glands  are  not  contracted.  As  ptyalism  —  i.e.,  pathologi- 
cally augmented  flow  of  saliva  due  to  other  causes,  such  as  neuroses, 
pregnancy,  helminthiasis,  etc.  —  as  a  rule  is  also  primarily  due  to 
autonomic  stimulation,  this  symptom  may  generally  be  relieved  by 
atropine. 

If  the  secretion  of  the  submaxillary  gland  be  stopped  by  a  dose  of  atropine 
just  large  enough  to  produce  this  effect,  it  may  be  excited  again  by  pilocarpine 
and  once  more  stopped  by  a  second  dose  of  atropine.  After  this  larger  dose  of 
atropine,  however,  it  is  hardly  possible  again  to  excite  secretion  by  further 
administration  of  pilocarpine.  It  is  thus  seen  that,  while  there  is  a  reciprocal 
antagonism  between  these  two  drugs,  the  affinity  of  atropine  for  the  autonomic 
nerve-endings  is  much  stronger  than  that  of  pilocarpine,  much  as  is  the  case 
with  the  relative  affinities  of  carbon  monoxide  and  oxygen  for  haemoglobin. 

Except  in  very  markedly  toxic  doses,  atropine  does  not  affect  that 
secretion  of  saliva  which  follows  stimulation  of  the  sympathetic.  Such 
may  be  induced  experimentally  by  the  intravenous  administration  of 
epinephrin  or  inhibited  by  morphine,  the  effect  of  the  latter  being 
probably  due  to  central  action. 

The  innervation  of  the  other  glands  in  the  mouth  is  essentially  similar  to 
that  of  all  the  true  salivary  glands.  In  them,  however,  stimulation  of  the 
autonomic  nerves  which  reach  them  through  the  facial  nerve  causes  a  more 
concentrated  secretion  while  stimulation  of  the  sympathetic  nerves  supplying 
them  results  in  a  more  dilute  secretion  (  Rethi  )  ,  but  to  drugs  they  reaqt  like  the 
salivary  glands. 


GASTRIC  SECRETION  165 

ELIMINATION  THROUGH  THE  SALIVARY  GLANDS. — The  chemical  com- 
position of  the  saliva  cannot  be  essentially  altered,  but  with  more 
abundant  flow  there  is  a  relative  decrease  of  its  organic  and  a  relative 
increase  of  its  inorganic  constituents,  particularly  of  the  carbonates 
(Fleckseder,  Binet).  Only  a  few  substances  foreign  to  the  body, 
such  as  hexamethylenamine  (Hanzlik)  and  the  iodides,  bromides,  and 
mercurial  and  lead  compounds,  are  excreted  by  the  salivary  glands, 
as  are  also  certain  alkaloids,  among  them  morphine  and  quinine,  which, 
by  their  bitter  taste,  betray  their  presence  in  the  secretion. 

BIBLIOGRAPHY 

Bayliss  and  Bradford:  Proc.  Physiol.  Soc.,  Journ.  of  Phys.,  1888,  vol.  6, 

Bernard,  Cl. :  Arch.  gen6r.  de  med.,  1853,  vol.  1,  p.  5. 

Binet:   Th&se  de  Paris,  1884. 

Fleckseder:   Ztschr.  f.  Heilk.,  1906,  vol.  27;  here  literature. 

Fiirth  u.  Schwarz:   Pfliiger's  Arch.,  1908,  p.  124. 

Hanzlik,  P.  J.:   Journ.  of  the  A.  M.  A.,  1910,  vol.  54,  p.  1940. 

Kinoshita:   Pfliiger's  Arch.,  1910,  vol.  132,  p.  607. 

Langley:    Journ.  of  Physiol.,  1885,  vol.  6,  p.  92. 

Marino  Zucco  and  Martini:   Arch.  Ital.  Biol.,  vol.  21,  1894. 

Rethi:   Sitz.-Ber.  d.  Akad.  d.  Wiss.  Wien  Okt.,  1905,  vol.  114. 

Schwarz  u.  Lederer:   Pfliiger's  Arch.,  1908,  p.  124. 

Tuczek:   Ztschr.  f.  Biol.,  1876,  vol.  12,  p.  534. 

THE  GASTRIC  SECRETION 

INNERVATION. — The  gastric  secretion  is  both  excited  and  inhibited 
by  two  sets  of  fibres  which  are  brought  to  it  in  the  vagus.  "While 
there  is  no  proof  that  stimuli  which  can  excite  secretion  reach  this 
organ  through  the  sympathetic  nerve,  by  analogy  with  the  mechanism 
of  the  pancreatic  secretion,  the  behavior  of  which  in  all  other  par- 
ticulars resembles  that  of  the  gastric  secretion,  it  may  be  assumed  as 
probable  that  they  do  so. 

CHEMICAL  STIMULATION  AND  INHIBITION. — The  secretion  of  the 
gastric  juice  is  determined  normally  by  the  chemical  action  of  the 
stomach  contents  on  the  gastric  mucous  membrane,  quite  indepen- 
dently of  this  nervous  mechanism,  which  is  controlled  by  reflexes 
acting  through  the  central  nervous  system,  the  extractives  of  meat 
(meat  soup),  albumoses,  peptones,  and  bread  acting  as  stimulants, 
while  fats  inhibit  it.  Acids  increase  while  alkalies  diminish  it. 

Even  this  chemical  action  on  the  mucous  membrane,  however,  is 
also  the  result  of  reflexes  which  occur  in  the  nervous  plexuses  of  the 
stomach  wall  and  are  not  affected  by  section  of  both  vagi.  Conse- 
quently it  may  be  concluded  that  they  are  independent  of  the  central 
nervous  system. 

Our  knowledge  of  these  and  other  very  important  facts  concerning 
the  secretion  of  gastric  juice  has  been  obtained  by  means  of  the  experi- 
cntal  methods  of  Paivlow.  This  physiologist  has  devised  a  method 
f  forming  a  "small  stomach,"  by  separating  a  portion  of  the  fundus 

the  stomach  from  the  rest  of  this  organ  in  such  a  fashion  that  it 


166  PHARMACOLOGY  OF  THE  DIGESTION 

forms  a  blind  sac  opening  through  the  abdominal  wall  but  still 
remaining  connected  with  the  large  stomach  by  nerves  and  vessels  and 
thus  receiving  all  the  nervous  impulses:  which  are  excited  locally  in  the 
large  stomach  or  which  originate  in  the  central  nervous  system.  The 
secretory  activity  of  this  small  stomach  gives  an  essentially  true  picture 
of  that  of  the  large  stomach. 

According  to  Starling  and  Edkins,  the  chemical  stimulation  of  the  secre- 
tory activity  of  the  stomach  is  due  to  the  direct  stimulation  of  the  gastric 
glands  by  secretin,  a  substance  formed  in  the  mucous  membrane  of  the  pylorus 
by  acid  or  by  products  of  digestion. 

DIRECT  ACTION  OF  DRUGS 

The  secretion  of  gastric  juice  may  be  excited  by  pilocarpine, 
choline,  etc.,  and  also  by  MORPHINE,*  and  may  be  temporarily  inhib- 
ited by  ATROPINE.  From  a  practical  point  of  view  the  action  of  pilo- 
carpine in  conditions  of  pathologically  diminished  gastric  secretion  is 
of  no  importance,  for  the  following  reasons :  Such  disturbance  of  func- 
tion results  either  from  disease  of  the  gastric  mucous  membrane 
(gastritis,  carcinoma,  etc.),  in  which  stimulation  through  the  vagus 
would  produce  no  effect  and  in  which  only  the  administration  of  pepsin 
and  HC1  could  be  of  value,  or  from  nervous  disturbances  (inhibitions), 
in  which  case  it  is  often  accompanied  by  a  normal  or  even  in- 
creased motility  and  compensatorily  increased  pancreatic  secretion 
(Cohnheim),  under  which  conditions  the  digestion  either  remains 
normal  and  demands  no  interference,  or  else  the  insufficiently  digested 
ingesta  rapidly  pass  into  the  intestine  and  cause  diarrhoea,  which 
would  only  be  aggravated  by  the  administration  of  drugs  like  pilocar- 
pine, which  stimulate  the  vagus.  In  such  cases  assistance  is  rather  to 
be  expected  from  morphine,  which  inhibits  the  motility  of  the  stomach 
and  at  the  same  time,  after  temporarily  inhibiting  the  gastric  secre- 
tion, increases  it  to  a  considerable  extent  (see  p.  189).  [While  the 
above  statement  is  theoretically  correct,  there  is  still  much  in  it  that  is 
too  hypothetical  to  permit  the  clinician  to  adopt  such  suggestions, 
particularly  as  the  use  of  morphine  would  be  extremely  dangerous  in 
chronic  conditions  of  subacidity  and  as  the  acute  cases  almost  invaria- 
bly respond  satisfactorily  to  other  methods  of  treatment. — TR.]  In 
this  connection  it  should  be  mentioned  that  in  chronic  morphinism  the 
gastric  secretion  gradually  and  progressively  diminishes  until  it  fails 
entirely,  re-establishing  itself  again  only  if  the  habit  be  abandoned 
(Hitzig). 

*  This  has  been  established  by  Riegel  in  dogs  with  a  Pawlow  small  stomach, 
and  also  under  various  conditions  in  man.  On  the  other  hand,  Leubuscher  and 
Schafer  found  after  oral  administration  of  morphine  normal  acid  values  but  after 
subcutaneous  administration  subnormal  values.  The  reason  for  these  contradic- 
tory findings  is  not  clear,  but  it  is  possible  that  they  are  due,  at  least  in  part, 
to  the  admixture  of  different  amounts  of  the  alkaline  saliva  (Bickel  u.  Pincus- 
sohn) . 


GASTRIC  SECRETION  167 

REFLEX  STIMULATION  BY  DRUGS. — A  sluggish  and  insufficient  secre- 
tion may  usually  be  stimulated  in  a  reflex  fashion  by  substances  with 
a  pronounced  taste  or  smell  and  which  stimulate  the  appetite.  Among 
these  may  be  mentioned  wine,  salt,  spices,  and  pepper,  as  also  certain 
substances  which  even  when  given  by  enema  produce  the  same  reflex 
effects  by  their  action  on  the  intestinal  mucous  membrane.  Such  are 
alcohol,  ethereal  oils  (Wallace  and  Jackson),  and  probably  many 
other  substances  which  act  as  mild  local  irritants. 

INHIBITION  OF  HYPERSECRETION. — Of  much  greater  importance  is 
the  relief  of  the  so-called  hyperacidity  of  the  gastric  juice,  which  is 
more  correctly,  however,  a  hypersecretion,  for,  as  Pawlow  has  shown, 
the  HC1  concentration  of  the  secretion  of  the  peptic  glands  is  never 
increased  above  the  normal.  The  apparent  hypersecretion,  however,  is 
often  due  to  nothing  else  than  an  accumulation  of  the  continually 
secreted  gastric  juice,  which,  in  cases  with  motor  insufficiency  and 
spasm  of  the  pylorus,  is  not  sufficiently  neutralized  by  saliva  from  the 
mouth  or  by  mucus  from  the  stomach  (Katschkowski) .  In  this 
connection  it  should  be  remembered  that  hyperacidity  itself  has  a 
tendency  to  cause  spasm  of  the  pylorus.  In  such  cases  the  best  drugs 
to  use  are  the  alkaline  carbonates,  calcined  magnesia,  lime  water,  etc., 
which  both  inhibit  the  secretion  and  also  neutralize  the  excess  of  acid. 
Lavage  of  the  stomach  is  also  at  times  indicated  in  these  conditions. 

If  as  the  result  of  motor  insufficiency  and  of  the  dilatation  of  the 
stomach,  which  usually  accompanies  insufficiency,  the  contents  of  the 
stomach  stagnate,  various  bacteria  may  multiply  rapidly  in  the 
stomach  and  produce  considerable  quantities  of  lactic,  butyric,  and 
acetic  acid.  Under  these  conditions,  although  magnesia  or  soda  will 
neutralize  these  acids  and  thus  temporarily  relieve  the  acid  eructations 
and  heart-burn,  their  use  favors  the  proliferation  of  bacteria  and  thus 
tends  to  aggravate  the  condition.  It  is,  therefore,  a  better  plan  to 
cleanse  the  stomach  by  lavage,  with  or  without  antiseptics  (Naunyn). 
Hypersecretion  associated  with  pyloric  spasm,  which  is  frequently 
present  in  cases  of  ulcer  of  the  stomach  and  which  interferes  with  the 
healing  of  the  ulcers,  may  often  be  relieved  by  a  long-continued  use  of 
atropine,  of  which  y2  to  2  mg.  should  be  given  by  needle  each  day 
(Tabor  a,  8 chick). 

It  may,  moreover,  be  concluded  that  the  secretion  of  the  gastric 
juice  will  be  diminished  by  all  substances  which  mechanically  diminish 
the  susceptibility  of  the  gastric  mucosa  to  the  chemical  stimuli  fur- 
nished by  the  food.  Indifferent  colloids,  like  solutions  of  gum  arabic 
and  starch,  or  fine  insoluble  powders,  such  as  bismuth  subnitrate, 
talcum,  and  the  like,  which  adhere  to  and  cover  the  wall  of  the 
stomach,  act  in  this  fashion.  [It  is  extremely  unlikely  that  these  pow- 
do  actually  adhere  to  and  cover  the  wall  of  the  stomach. — TR.] 

ether  local  anaesthetics,  such  as  cocaine,  nirvanin,  etc.,  also  indi- 
ctly  diminish  gastric  secretion  has  not  yet  been  determined. 


168  PHARMACOLOGY  OF  THE  DIGESTION 

BIBLIOGRAPHY 

Bickel  u.  Pincussohn:   Sitz.-Ber.  d.  Berl.  Akad.  d.  Wiss.,  1907,  No.  52. 

Edkins:  Journ.  of  Physiol.,  1906,  vol.  34. 

Katschkowski :   Pfliiger's  Arch.,   1901,  vol.  84. 

Leubuscher  u.  Schafer:   Deut.  med.  Woch.,  1892,  No.  46. 

Naunyn:  Deut.  Arch.  f.  klin.  Med.,  1882. 

Pawlow:   Die  Arb.  d.  Verdauungsdriisen,  1898. 

Pawlow:  Ergebn.  d.  Physiol.,  1902,  vol.  1,  p.  246. 

Riegel:  Ther.  d.  Gegenw.,  1900. 

Riegel:  Ztschr.  f.  klin.  Med.,  1899,  No.  37. 

Schick:   Wien.  klin.  Woch.,  1910,  No.  34. 

Tabora:  Miinchn.  med.  Woch.,  1908,  No.  39. 

Wallace  and  Jackson:  Am.  Journ.  of  Physiol.,  1903,  vol.  8. 

PANCREATIC  SECRETION 

As  the  pancreatic  secretion  is  under  the  influence  of  the  same 
autonomic  and  sympathetic  innervation  as  is  that  of  the  stomach, 
its  behavior  under  the  influence  of  drugs  is  in  most  particulars  the 
same  as  that  of  the  gastric  secretion,  with  the  exception  that  fats  cause 
a  stimulation  of  the  pancreatic  secretion. 

Its  secretion  may  be  reflexly  excited  by  stimulating  the  mucous 
membrane  of  the  intestine,  particularly  that  of  the  duodenum,  by 
pungent  substances,  such  as  mustard,  pepper,  and  the  like ;  but  it  may 
also  be  excited,  independently  of  other  nervous  control,  by  the  direct 
chemical  stimulation  of  the  terminal  organs  (secretory  nerve-endings 
or  secretory  cells?)  (Gottlieb).  The  specific  chemical  stimulant  for 
this  gland  is  a  substance,  named  secretin  by  its  discoverers,  Sterling 
and  Bayliss,  which  is  formed  in  the  mucous  membrane  of  the  small 
intestine  under  the  influence  of  hydrochloric  acid.  Consequently,  any 
hydrochloric  acid  which  passes  into  the  small  intestine  stimulates  the 
secretion  of  the  pancreatic  juice  and  of  bile,  while  alkalies  inhibit 
them. 

That  portion  of  the  pancreatic  secretion  which  is  excited  by  secretin 
is  not  influenced  by  atropine  and  pilocarpine,  but  these  drugs  do  in- 
fluence that  portion  of  this  secretion  which  results  from  the  excitation 
of  the  vagal  secretory  nerve-ending  in  the  pancreas.  This  is  excited 
by  pilocarpine  and  choline  *  and  inhibited  by  morphine  and  by  small 
doses  of  atropine.  Larger  (ten  times  larger)  doses  of  atropine,  how- 
ever, cause  a  profuse  secretion  of  pancreatic  juice  in  the  dog  (Wert- 
heimer-Lepage,  Cohnheim  u.  ModrakowsJci) .  For  this  latter  effect  no 
satisfactory  explanation  can  be  given  at  present,  but  it  is  perhaps  due 
to  a  depression  of  the  vagal  inhibition  of  the  secretion  (Popielski) . 

In  cases  in  which  duboisine,  a  drug  whose  action  resembles  that  of  atropine, 
had  been  used  repeatedly  as  a  means  of  quieting  insane  patients,  it  has  been 
observed  that  the  patients  lose  weight  markedly  and  become  ill-nourished,  a 

*  Choline  influences  the  pancreatic  secretion  in  two  different  ways.  Periph- 
erally it  excites  the  vagal  secretory  nerve-endings  and  centrally  it  excites  the 
nerves  which  inhibit  this  secretion  and  which  pass  to  the  pancreas  in  the 
vagus  trunk.  It  therefore,  in  small  doses,  usually  inhibits  this  secretion,  and 
in  large  doses,  after  temporarily  inhibiting  secretion,  stimulates  it  ( Schwarz ) . 


PANCREATIC  SECRETION  169 

result  which  is  possibly  due  to  the  inhibition  of  the  pancreatic  secretion  resulting 
from  the  use  of  this  drug  (Marandon  de  Montyel).  As  early  as  1863,  V.  Grafe 
stated  that  when  atropine  instillations  were  frequently  repeated  there  resulted 
a  "  general  irritable  weakness  and  impairment  of  the  power  of  assimilation." 

INTERNAL  SECRETION. — In  addition  to  the  secretion  which  is  poured 
out  into  the  intestine,  the  pancreatic  gland,  in  all  probability,  pro- 
duces an  internal  secretion  which  is  carried  throughout  the  body 
by  the  blood,  and  which  is  of  decisive  importance  in  connection  with 
the  utilization  of  the  carbohydrates,  as  well  as  for  the  normal  absorp- 
tion of  the  fats.  When  this  internal  secretion  fails,  as  in  cases  of 
pathological  degeneration  or  experimental  extirpation  of  the  pancreas, 
severe  diabetes  develops  and,  as  a  rule,  the  absorption  of  fat  is  mark- 
edly impaired.*  The  oral  administration  of  pancreas  preparations 
appears  in  these  cases  to  improve  the  absorption  of  fat,  but  produces 
no  favorable  effects  whatever  on  the  diabetes.  Thus  far  we  know  of 
no  drugs  or  oilier  agents  which  increase  or  diminish  or  in  any  other 
fashion  influence  the  internal  secretion  of  the  pancreas. 

BIBLIOGRAPHY 

Cohnheim  u.  Modrakowski:  Z.  f.  physiol.  Chem.,  1911,  vol.  71,  p.  273. 

Fleckseder:   Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59,  p.  407. 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  33. 

v.  Grafe:   Grafe's  Arch.,  1863,  vol.  9,  Part  2,  p.  71. 

Lombroso:   Pfliiger's  Arch.,  vol.  112,  1906. 

Lombroso:    Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56,  p.  357. 

Marandon  de  Montyel:   Bull,  de  Ther.,  1894,  vol.  63. 

Modrakowski:   Pfliiger's  Arch.,  1906,  vol.  114. 

Popielski:   Zentralbl.  f.  Phys.,  1896. 

Schwarz,  0.:   Zentralbl.  f.  Physiol.,  1910,  vol.  23,  No.  11. 

Starling  and  Bayliss:   Journ.  of  Physiol.,  1902,  vol.  28,  p.  325. 

Wertheimer-Lepage :   De  1'action  de  quelques  alcaloides,  etc.,  Lille,  1904. 

THE  SECRETION  OF  THE  BILE 

The  secretion  of  bile  is  controlled  by  the  same  nervous  and  chemi- 
cal influences  as  is  that  of  the  pancreas.  Under  the  influence  of 
the  ingestion  of  food  these  two  secretions  run  along  almost  exactly 
parallel  (see  Fig.  12),  both  being  stimulated  by  secretin.  The  expul- 
sion of  the  bile  from  the  gall-bladder  is  accelerated  by  drugs  which 
stimulate  the  vagus  and  inhibited  by  those  which  stimulate  the  sympa- 
thetic. 

Under  the  influence  of  pilocarpine  the  gall-bladder  contracts  and  the 
sphincter  of  the  ductus  choledochus  closes,  but  a  little  later  relaxes  completely. 
Atropine,  on  the  other  hand,  causes  a  relaxation  of  the  gall-bladder  and  of 
this  sphincter  (Doyon),  an  action  which  is  therapeutically  of  importance  in  con- 
nection with  gall-stone  colic,  which  probably  is  produced  by  contraction  of  the 
bladder  and  not  by  that  of  the  duct  (Aschoff). 

*  This  is  not  always  the  case,  however,  for  when  the  pathological  condition 
develops  slowly  the  absorption  of  the  fat  may  remain  normal  or  after  temporary 
impairment  may  become  normal  again  (Fleckseder,  Lombroso). 


170  PHARMACOLOGY  OF  THE  DIGESTION 

CHOLOGOGUES. — Of  particular  importance  to  the  physician  is  the 
question  whether  or  not  there  are  any  drugs  or  other  means  of 
appreciably  increasing  the  secretion  of  bile  without  producing  other 
undesirable  effects. 

The  drugs  of  the  PILOCARPINE  group  are  not  suitable  for  this  pur- 
pose, as  they  affect  all  the  organs  of  the  autonomic  system.  Further, 
they  simply  cause  the  bile  to  flow  out  of  the  gall-bladder  more  rapidly 
without  augmenting  its  secretion  by  the  liver.  However,  certain  sub- 
stances are  known  to  be  specific  stimulants  of  this  secretion.  These 
are  bile  itself  or  the  salts  of  the  biliary  acids,  soaps,  albumoses,  dilute 
HCl  (Weinberg)  and  to  a  lesser  degree  the.  benzoate  and  the  salicy- 
lates  of  soda.  Neither  soda  nor  Glauber's  salt  or  other  cathartics  pro- 
duce any  demonstrable  increase  in  the  secretion  of  bile,  while  calomel 
in  cathartic  doses  actually  inhibits  it  (Prevost  and  Binet,  Doyon  and 
Dufourt}. 

Gall-stone  patients  are  commonly  advised,  often  with  benefit,  to  use 
Carlsbad  salts  or  sodium  oleate  (under  various  trade  names)  or  various 
mixtures  of  cathartics.  (One  popular  one,  chologen,  contains  calomel,  podo- 


FIQ.  12. — Secretion  after  taking  food:    a,  pancreatic  secretion  after  milk;  6,  after  meat; 
c,  after  bread;  01,  gastric  secretion  after  milk;  bi,  after  meat;  ci,  after  bread. 

phyllin,  and  an  ethereal  oil.)  It  is  difficult  to  determine  whether  these  drugs 
are  actually  curative  or  not.  Probably  the  benefit  which  often  follows  their  use 
is  'chiefly  due  to  their  power  of  curing  or  relieving  the  inflamed  and  irritable 
condition  of  the  mucous  membrane  of  the  gall-bladder,  which  renders  it  tender 
and  causes  spasmodic  contractions  of  the  gall-bladder,  by  which  gall-stones, 
which  may  be  present  without  causing  symptoms,  are  forced  into  the  duct, 
causing  colic  and  obstructive  jaundice.  In  this  connection,  it  is  to  be  remem- 
bered that  chronic  inflammation  of  the  mucous  membrane  of  the  gall-bladder 
is  always  a  necessary  preliminary  condition  for  the  production  of  the  gall-stones 
themselves  (lit.,  Naunyn,  Herter).  It  is  difficult  to  imagine  in  what  manner 
Carlsbad  salts  can  exert  any  favorable  effects  on  the  mucous  membrane  of  the 
gall-bladder,  for  probably  neither  the  neutral  salts  nor  the  carbonates  are 
excreted  in  the  bile. 

ELIMINATION  AND  ANTISEPSIS. — Different  drugs  and  poisons  are  secreted 
by  the  bile,  among  others  Cu,  Pb,  Hg  (Langer),  amyl  alcohol,  methylene  blue 
(Brauer),  menthol  (/?.  Stern),  and  hexamethylenamine  (Crowe).  Of  the  last 
two,  when  administered  in  sufficient  doses  (of  menthol  6.0  gm.,  of  hexamethyl- 
enamine 5.0  gm.  per  diem),  enough  is  secreted  to  sterilize  the  bile. 


SECRETION  OF  BILE  171 

When  the  bile  is  prevented  from  joining  the  pancreatic  juice  in  the 
intestine,  this  latter  cannot  by  itself  properly  prepare  the  fats  for 
absorption,  so  that  the  stools  contain  large  amounts  of  fat.  It  is 
quite  remarkable  that  under  these  conditions  the  administration  of 
bile  with  the  food  is  of  no  benefit.  Apparently  the  pancreatic  juice 
and  the  bile  must  be  very  thoroughly  mixed  together  and  in  exactly 
correct  proportions  in  order  that  this  function  shall  be  properly 
performed,  and  apparently  such  a  mixing  cannot  be  attained 
artificially. 

OTHER  LIVER  FUNCTIONS. — The  manufacture  of  bile  is  only  one 
of  the  many  functions  of  the  liver,  which  is  an  organ  in  which  analytic 
and  synthetic  reactions  of  most  varying  nature  take  place.  Among 
these  functions  one  of  the  most  important  is  that  of  transforming  the 
carbohydrates  into  glycogen  and  storing  them  up  as  such,  and  of  form- 
ing and  supplying  glucose  to  the  body  as  it  is  needed.  How  these 
two  chemical  processes  are  controlled  is  unknown,  but  it  is  very 
probable  that  the  formation  of  glycogen  is  accomplished  with  the  aid 
of  the  internal  secretion  of  the  pancreas,  and  that  the  transformation 
of  glycogen  into  glucose  takes  place  under  the  influence  of  epinephrin, 
the  internal  secretion  of  the  suprarenals. 

Other  chemical  functions  of  the  liver,  such  as  the  anabolism  of 
fats  and  proteids,  are  probably  markedly  influenced  by  the  internal 
secretion  of  the  thyroid,  iodothyrin,  but  concerning  this  we  know  com- 
paratively little.  From  all  that  is  known,  however,  it  appears  that,  in 
contrast  to  the  function  of  the  true  glands,  the  activity  of  the  liver  is 
regulated  not  by  secretory  nerve  impulses  but  by  chemical  stimuli, 
which  are  supplied  by  specific  substances,  Starling's  hormones,  and 
also  by  the  composition  and  amount  of  the  blood  supply. 

BIBLIOGRAPHY 
Aschoff:  Verb.  d.  Path.  Ges.,  1906. 

Brauer:   Ztschr.  f.  physiol.  Chem.,  1904,  vol.  40,  p.   182. 
Crowe,  J.:   The  Johns  Hopkins  Hosp.  Bull.,  1908,  vol.  19,  No.  205. 
Doyon  et  Dufourt:  Arch.  d.  Phys.,  1897. 
Doyon:   Etude  analytique,  etc.,  Lyon,  1893, 
Herter:   Trans,  of  the  Congr.  of  Am.  Phys..  1903,  vol.  6. 
Langer:   Ztschr.  f.  exp.  Pathol.  u.  Ther.,  1906,  vol.  3. 
Naunyn:   Cholelithiasis. 

Pawlow:   Das  Experiment,  Wiesbaden,  1900,  p.  13. 
Prevost  et  Binet:   Compt.  rend.,  1888,  106. 

Stern,  R.:    Ztschr.  f.  Hygiene  u.  Inf.-Krankh.,  1908,  vol.  59,  p.  129. 
Weinberg:  Zbl.  ges.  Physiol.  u.  Pathol.  d.  Stoffw.  N.  F.,  6,  No.  1. 

THE  SECRETION  OF  THE  INTESTINAL  JUICE 

The  secretion  of  the  intestinal  juice — the  chief  constituents  of 
which  are,  in  the  duodenum,  the  ferment,  enterokinase,  which  activates 
trypsin,  and,  in  the  jejunum,  invertase  and  erepsin,  which  possesses 
the  power  of  decomposing  the  albumoses — is  excited  by  local,  mechani- 
cal, or  chemical  stimulation  of  the  intestinal  mucous  membrane,  par- 


172  PHARMACOLOGY  OF  THE  DIGESTION 

tieularly  by  the  pancreatic  juice  and  by  the  ingesta.  Up  to  the  present, 
the  extent  to  which  the  central  nervous  system  controls  this  secretion 
has  not  been  sufficiently  investigated,  and  the  same  is  true  as  regards 
the  action  of  drugs.  Consequently,  we  know  little  of  the  manner  in 
which  this  secretion  may  be  affected  by  pharmacological  agents. 

The  mucous  glands,  which  are  present  throughout  the  whole 
extent  of  the  alimentary  tract,  are  stimulated  to  secretion  by  the  alka- 
line carbonates  and  are  inhibited  by  acids  and  astringents.  These 
latter  drugs  also  precipitate  and  render  insoluble  proteid  substances 
dissolved  or  suspended  in  the  fluid  contents  of  the  intestine,  and 
consequently  they  increase  the  consistency  of  the  intestinal  contents 
and  render  them  drier. 

ELIMINATION  THROUGH  THE  INTESTINE. — As  has  already  been  men- 
tioned in  connection  with  the  secretion  of  saliva  and  of  bile,  various 
substances  for  which  the  body  has  no  further  use,  such  as  C'a,  Fe, 
phosphoric  acid,  and  organic  detritus  and  various  foreign  substances, 
are  eliminated  in  the  different  digestive  juices.  It  is  thus  apparent 
that  the  mucous  membranes  of  the  stomach  and  intestine  are  organs 
of  excretion,  a  fact  which  is  of  particular  importance  in  connection 
with  certain  poisons.  Thus,  compounds  of  the  heavy  metals,  Pb,  Cu, 
Hg,  Bi,  Fe,  and  Mn,  and  arsenic  and  antimony  and  the  halogen  salts 
of  the  alkalies,  are  excreted  in  this  fashion,  as  are  also  morphine  in 
considerable  extent  and,  to  a  less  degree,  other  alkaloids  and  the 
drastic  cathartics,  aloin  and  podophyllin,  as  also  bacterial  toxins  and 
snake  venom.  The  harmful  actions  on  the  intestine  which  result 
from  the  administration  of  many  of  these  substances,  even  when 
administered  subcutaneously  or  intravenously,  is  due  to  their  excretion 
by  this  route. 

ABSORPTION  IN  THE  ALIMENTARY  CANAL 
IN  THE  STOMACH 

Absorption  occurs  throughout  the  whole  intestine,  starting  in  the 
duodenum  and  ending  in  the  rectum.  With  the  exception  of  those 
substances  which  are  soluble  in  the  lipoids,  the  mucous  membrane  of 
the  mouth  and  of  the  stomach  does  not  absorb  mentionable  amounts 
either  of  water  or  of  food-stuffs  or  other  substances  in  aqueous 
solution  (Karmel,  Meltzer).  Lipoid  soluble  substances  readily  pene- 
trate the  epithelial  covering  and  more  or  less  rapidly  enter  the 
blood,  so  that  it  is  possible  that  such  substances  as  nicotine  or  phenol 
may  be  quite  readily  absorbed  by  the  mucous  membrane  of  the 
mouth  in  amounts  sufficient  to  cause  a.  systemic  poisoning.  The 
slight  power  of  the  stomach  to  absorb  substances  which  are  not  soluble 
in  the  lipoids — for  example,  most  salts  of  the  organic  and  inorganic 
bases — may  be  of  pharmacological  importance  in  cases  with  motor 
insufficiency  of  the  stomach,  as  a  result  of  which  the  gastric  contents 


ABSORPTION  IN  STOMACH  173 

remain  for  many  hours  in  the  fundus  of  the  stomach,  for  under  such 
conditions  the  expected  effects  from  medicines  administered  by  mouth 
may  not  occur  or  may  at  least  be  very  markedly  retarded.  The  same 
result  must  naturally  ensue  if  the  motor  activity  of  the  stomach  has 
been  inhibited  by  such  drugs  as  morphine  or  epinephrin,  in  which 
case  the  gastric  contents  do  not  pass  on  into  the  duodenum,  in  which, 
as  already  stated,  absorption  really  begins. 

ACCELERATION  OF  ABSORPTION. — If  the  lipoid  structure  of  the 
superficial  layer  of  the  mucous  membrane  be  loosened  or  softened, 
water  and  salts,  sugar,  peptones,  etc.,  in  solution  are  able  to  pass 
into  it  more  readily,  and  consequently  may  be  absorbed.  This  is  appar- 
ently the  explanation  for  the  fact  that  fluids  containing  alcohol  or 
carbonic  acid  and  substances  dissolved  in  them  are  absorbed  from  the 
stomach,  although  only  in  small  quantities  (v.  Tappeiner,  Hirsch, 
v.  Mering).  According  to  Brandl,  pungent  irritating  substances  like 
oil  of  mustard  or  of  peppermint,  or  pepper,  increase  absorption.  As 
this  is  not  due  to  the  hyperasmia  as  such,  which  is  caused  by  them, 
it  must  be  due  to  a  chemical  change  in  the  cells,  a  cytolytic  action, 
altering  their  permeability. 

Bitters  do  not  directly  favor  absorption  from  the  stomach,  although 
they  cause  hyperaemia  of  the  mucous  membrane,  but  when  taken  an 
hour  before  eating  it  is  claimed  that  they  do  so  (Jodlbauer) .  In  dogs 
large  doses,  more  especially  if  repeatedly  administered  during  a  con- 
siderable period,  apparently  retard  the  emptying  of  the  stomach  and 
consequently  also  retard  the  absorption  of  the  food  from  the  intestine, 
but  small  doses  apparently  accelerate  both  these  processes  (Heubner). 

RETARDATION  OP  ABSORPTION. — Mucilaginous  substances,  such  as 
gum  arabic,  starch,  and  pectin,  markedly  diminish  the  resorptive 
power  of  the  stomach  (Brandl). 

ABSORPTION  IN  THE  INTESTINE 

The  intestinal  mucous  membrane  absorbs  not  only  lipoid  soluble 
substances,  but  also  those  insoluble  in  the  lipoids  yet  soluble  in  water. 
Most,  but  not  all,  of  the  effective  forces  to  which  this  absorption  is  due 
are  known  to  us,  and  are  diffusion  and  osmosis  on  the  one  hand  and 
nitration  pressure  on  the  other.  The  latter  is  apparently  of  sub- 
ordinate importance,  and  is  furnished  partly  by  the  pressure  of  the 
muscle  of  the  intestinal  wall  and  partly  by  the  pumping  action  of 
the  muscles  of  the  villi.  Contraction  of  the  intestinal  vessels  retards, 
and  dilatation  accelerates  absorption  (Sollmann,  Hanzlik  and  Pitcher) . 
In  very  general  terms  it  may  be  stated  that  lipoid  soluble  substances 
are  incomparably  more  readily  and  rapidly  absorbed  than  those  insolu- 
ble in  the  lipoids,  and  in  general  in  direct  proportion  to  this  solubility. 

Hdber,  by  his  very  ingenious  experiments,  has  shown  that  very  probably 
ie  path  of  absorption  for  substances  which  are  insoluble  in  lipoids  lies  be- 
veen  the  cells,  but  for  those  soluble  in  lipoids  through  the  cells  themselves, 


174  PHARMACOLOGY  OF  THE  DIGESTION 

the  absorption  occurring  in  the  former  instance  intercellularly,   in  the  latter 
intracellularly. 

It  has  not  been  definitely  established  just  how  the  fats,  which  are  insoluble 
in  water,  are  absorbed,  but  it  is  probable  that  they  are  first  saponified  or  else, 
like  the  fat  in  the  blood-serum,  are  rendered  soluble  by  chemical  union  with 
lecithin  and  proteids  (Miescher).  However,  recent  observations  (W.  Croner) 
indicate  that  in  the  dog  a  large  portion  of  the  fat  is  absorbed  from  the  small 
intestine  in  a  state  of  emulsification  and  is  not  first  saponified,  and  that  larger 
portions  are  absorbed  in  the  lower  than  in  the  upper  segment,  while  the 
absorption  of  the  saponified  portion  occurs  only  in  the  lower  segment.  After 
absorption  the  fats  pass  into  the  intestinal  lymphatics  and  mesenteric  veins. 

COD-LIVER  OIL  enjoys  a  peculiar  reputation  as  a  food  and  as  a 
curative  agent.  To  it  have  been  attributed,  partly  because  of  the 
presence  in  it  of  an  inconstant  and  very  small  amount  of  iodine  or  of 
certain  basic  substances  (aselline,  etc.),  curative  properties  in  tuber- 
culosis, scrofula,  rickets,  and  other  diseases.  Certainly  established 
in  regard  to  it  are  the  two  facts,  that  it  is  more  readily  and  per- 
manently emulsified  than  other  fats,  a  property  not  due  entirely  to  its 
containing  free  fatty  acids,  and  that  it,  especially  before  purification, 
is  much  better  absorbed  from  the  intestine  than  other  fats  (Gad, 
Marpmann,  Naumann,  Croner} . 

These  properties  are  sufficient  to  explain  its  value  as  a  very  efficient, 
because  very  digestible,  means  of  improving  digestion,  but  are  not 
sufficient  to  explain  its  other  real  or  fancied  curative  properties'.  As 
is  well  known,  cod-liver  oil,  even  the  official  purified  oil,  has  a  most 
repulsive  taste,  which  cannot  be  entirely  corrected  by  the  addition 
of  flavoring  agents.  Perhaps  impregnation  with  carbonic  acid  is  the 
•best  manner  of  securing  this.  Lipanin  (pure  olive  oil  with  6  per  cent, 
oleic  acid),  recommended  as  an  agreeably  tasting  substitute,  is  utilized 
much  more  poorly  than  cod-liver  oil  and  even  than  pure  olive  oil. 

The  saturated  non-volatile  hydrocarbons,  the  paraffins,  which  can  in  no 
way  be  brought  into  solution  in  water,  are  not  absorbed  from  the  alimentary 
canal. 

ABSORPTION  OF  SALTS 

The  rate  of  absorption  of  the  lipoid  insoluble  substances,  such  as 
the  inorganic  and  organic  salts,  the  sugars,  amido  acids,  etc.,  in 
general  runs  parallel  with  their  rate  of  diffusion.  With  isotonic 
and  slightly  hypertonic  solutions  of  neutral  salts,  the  rate  of  absorp- 
tion increases  with  their  anions  as  follows :  HPO4  <  SO*  <  N03  <  Br  <  Cl, 
and  with  their  kations,  Mg<Ca<Na<K,  and  exactly  the  same  order 
holds  good  for  their  observed  rates  of  diffusion.  With  the  salts 
of  organic  acids  also  the  rates  of  absorption  are  found  to  vary  pro-, 
portionately  to  their  diffusibility,  but  here  their  lipoid  solubility  in- 
fluences their  absorbability  to  some  extent  (Hober) . 

In  general  it  may  be  stated  that  the  salts  of  sodium,  potassium, 
and  ammonium  with  monobasic  acids  are  readily  diffusible  and  absorb- 
able,  while  those  with  the  polybasic  acids  diffuse  slowly  and  are  also 


ABSORPTION  FROM  INTESTINE  175 

absorbed  with  difficulty  ( Wallace  and  Cushny')*  The  same  parallelism 
holds  good  in  general  for  non-electrolytes,  such  as  the  various  sugars 
and  ammo-acids,  but  salts,  such  as  the  fluorides  or  oxalates  or  the  salts 
of  barium,  the  anions  or  kations  of  which  are  toxic  to  the  intestinal 
epithelium,  behave  quite  differently,  being  absorbed  much  more  slowly 
than  would  be  expected  from  their  diffusibility.  The  permeability 
and  resorptive  power  of  the  intestinal  mucous  membrane  may  be  very 
markedly  impaired  by  the  toxic  action  of  other  substances  (Scanzoni), 
but  no  one  has  thus  far  investigated  whether  this  be  due  to  a  chemical 
alteration  of  the  colloid  membrane  formed  by  the  epithelial  lining 
or  to  the  paralysis  of  the  active  physiological  factors  such  as  the 
muscles  of  the  villi.  As  this  can  be  properly  discussed  only  after 
discussion  of  the  mechanism  of  the  digestive  processes,  it  will  be 
taken  up  later,  as  will  the  pharmacological  significance  of  absorption 
in  the  intestine  in  the  section  on  cathartics. 

As  the  blood  from  the  whole  of  the  small  intestine  and  of  the  colon 
passes  through  the  portal  vein  into  the  liver,  while  the  rectum  is 
drained  by  the  hemorrhoidal  plexus,  from  the  middle  portion  of  which 
the  blood  passes  directly  into  the  general  circulation,  it  is  not  a  matter 
of  indifference  from  which  portion  of  the  alimentary  canal  food  or 
drugs  are  absorbed.  This  is  the  reason  why  powerful  poisons,  such  as 
morphine,  strychnine,  and  particularly  carbolic  acid,  when  adminis- 
tered by  rectum  may  under  certain  conditions  cause  more  rapid  or 
pronounced  poisoning  than  when  they  are  introduced  into  the  stomach, 
in  which  case  they  must  first  pass  through  the  liver  and  only  gradually 
enter  the  general  circulation,  particularly  as  the  poisonous  effects  of 
most  toxic  substances  are  markedly  lessened  by  passage  through  the 
liver,  partly  as  a  result  of  being  chemically  changed  by  conjugation 
with  sulphuric  acid,  etc.,  and  partly  as  a  result  of  absorption  and 
consequent  retarded  entrance  into  the  general  circulation  (see  Curare, 
Potassium  Salts,  etc.,  and  also  Rothberger  u.  Winterberg). 

BIBLIOGRAPHY 

Brandl:   Ztschr.  f.  Biol.,  1883,  vol.  29. 

Croner,  W.:   Biochem.  Ztschr.,  1909,  vol.  23,  p.  97. 

Gad:  Arch.  f.  Physiol.,  1878,  p.  181. 

Heubner:  Therap.  Monatshefte,  1909,  No.  6. 

Hober:  Hdb.  d.  physik.  Chem.  u.  Med.,  von  Koranyi  u.  Richter,  1907. 

Joanovicz  u.  E.  Pick:   Wien.  klin.  Woch.,  1910,  No.  16. 

Jodlbauer:  Arch,  intern,  de  Pharmacodyn.,  1902,  vol.  10. 

Karmel:  Diss.  Dorpat,  1873. 

Marpmann:  Miinchn.  med.  Woch.,  1888,  p.  485. 

Meltzer:  Am.  Journ.  Med.  Sc.,  1889. 

v.  Mering:   Verh.  d.  Kongr.  f.  inn.  Med.,  1894. 

These  authors  have  called  attention  to  another  parallelism  in  connection 
with  these  substances.     The  anions  of  the  easily  absorbed  salts  form  readily 
soluble  salts  with  calcium,  while  those  of  the  salts  which  are  absorbed  slowly 
insoluble  calcium  salts.     This,  however,  does  not  hold  good  for  all  cases, 
or   potassium    ferrocyanide    is    slowly   absorbed   although    calcium    ferrocyanide 
'  readily  soluble  in  water. 


176  PHARMACOLOGY  OF  THE  DIGESTION 

Miescher:  Arb.,  vol.  1,  p.  321,   1897. 

Naumann:   Arch.  d.  Heilk.,  1865,  vol.  6,  p.  536. 

Kothberger  u.  Winterberg:  Arch,  intern,  de  Pharmacodyn.,  1905,  vol.  15;   here 

compl.  literature. 
Scanzoni:   Ztschr.  f.  Biol.,  1896. 
Sollmann,  T.,  Hanzlik  u.  Pilcher:  Journ.  of  Pharm.  and  Exp.  Ther.,  1910,  vol.  1, 

p.  409. 

v.  Tappeiner:  Ztschr.  f.  kl.  Med..,  1893. 
Wallace  u.  Cushny:  Pfliiger's  Arch.,  1899,  vol.  77,  p.  202. 
Wallace  u.  Cushny:  Amer.  Journ.  Physiol.,  1898,  vol.  1,  p.  411. 

II.  THE  MECHANICS  OF  DIGESTION 
DEGLUTITION 

The  first  of  these  are  mastication  and  deglutition,  which  latter  may 
be  voluntarily  inaugurated  by  pressing  the  root  of  the  tongue  against 
the  palate,  but  which  when  once  started  is  reflexly  completed  even 
against  the  will,  the  peristaltic  action  of  the  oesophagus  pushing  its 
contents  downward  and  the  cardia  opening  to  permit  their  entrance 
into  the  stomach.  The  chief  nervous  centre  presiding  over  this  act 
lies  in  the  medulla,  and  receives  its  afferent  impulses  from  definite 
portions  of  the  throat,  the  so-called  swallowing  points,  which  are 
specifically  innervated  by  sensory  nerves  derived  from  the  trigeminal, 
superior  laryngeal,  and  glossopharyngeal  nerves,  and  which  are  stimu- 
lated by  contact  with  fluids  or  solids. 

PHARMACOLOGICAL  INTERFERENCE  WITH  DEGLUTITION. — If  these 
points  are  benumbed  by  the  application  of  cocaine,  such  stimulation 
no  longer  causes  swallowing,  an  effect  which  at  times  may  be  desirable 
during  operations  on  the  pharynx  or  larynx.  During  general  anaes- 
thesia or  in  deep  morphine  narcosis,  this  centre  becomes  so  unexcitable 
that  stimulation  of  it  results  in  swallowing  movements  only  in  the 
muscles  of  the  pharynx  but  not  in  those  of  the  oesophagus  or  cardia 
(Meltzer).*  This  should  be  remembered  when  treating  narcotized 
individuals;  for  liquids  administered  to  them  should  not  be  simply 
poured  into  the  mouth,  but  should  be  introduced  into  the  stomach 
through  the  stomach-tube.  In  general  anaesthesia  the  secretion  of 
saliva  should  either  be  suppressed  by  such  drugs  as  atropine  or  scopo- 
lamine  or  care  should  be  taken  to  remove  it  from  the  throat,  for  the 
abolition  of  the  swallowing  reflex  leaves  the  glottis  open,  so  that  the 
saliva  may  flow  into  the  lungs  and  cause  an  inhalation  pneumonia. 

Deglutition  may  also  be  completely  or  partially  prevented  by 
paralysis  of  the  motor  nerves  in  some  or  all  of  the  muscles  of  deglu- 
tition. Pharmacologically  such  paralysis  may  be  caused  by  drugs  with 
a  curare  action,  which  paralyze  the  striped  muscle  in  the  upper  por- 
tion of  the  oesophagus,  or  by  autonomic  paralyzants  like  atropine, 
which  prevent  the  action  of  the  smooth  muscles  of  the  lower  oesophagus 

*  Am.  Journ.  of  Physiol.,  1899,  vol.  2,  p.  266. 


EMESIS  177 

and  of  the  cardia.  This  is  of  significance  in  connection  with  the 
symptoms  of  belladonna  poisoning.  This  action  of  atropine  would 
also  justify  its  employment  to  relax  oesophageal  or  cardial  spasm. 

MOVEMENTS  OF  THE  STOMACH 

In  the  muscular  movements  of  the  stomach  one  may  distinguish 
peristaltic  and  antiperistaltic  movements,  which  latter  occur  during 
vomiting,  a  discussion  of  which  follows: 

Vomiting,  like  swallowing,  is  a  reflex  phenomenon  in  which  numer- 
ous smooth  and  striped  muscles  cooperate  together  in  an  orderly  fash- 
ion. The  pylorus  being  closed,  the  contraction  of  the  antrum  of  the 
pylorus  drives  the  stomach  contents  into  the  fundus,  which,  previously 
and  independently  of  its  fulness,  actively  dilates  as  a  result  of  relaxa- 
tion of  its  tone  (Frantzen) .  At  the  same  time  the  cardia  opens,  so  that 
the  spasmodic  contraction  of  the  diaphragm,  of  all  the  abdominal 
muscles,  and  also  of  the  muscles  of  the  fundus,  all  starting  at  the  same 
time,  expel  the  stomach  contents  through  the  oasophagus  and  pharynx. 
The  coordination  of  these  various  acts  is  controlled  by  a  centre  lying 
in  the  medulla,  the  so-called  vomiting  or  emetic  centre. 

Emetic  Centre. — A  region  has  been  discovered  by  Thumas  in  the  lower 
layers  of  the  medulla  below  the  calamus  scriptorius,  electric,  mechanical,  or 
specific  stimulation  of  which  induces  vomiting.  This  appears  to  be  a  coordinat- 
ing centre,  under  whose  influence  the  centres  for  the  innervation  of  the  cardia  and 
of  the  stomach,  which  lie  in  the  caudate  nucleus  and  in  the  region  of  the  corpora 
quadrigemina  (Hlasko),  and  the  reflex  centres  controlling  the  abdominal  respira- 
tory muscles,  which  are  also  involved  in  vomiting,  are  excited  to  a  general 
coordinated  action.  Elimination  of  one  of  these  centres — as  occurs,  for  example, 
if  the  corpora  quadrigemina  be  destroyed  (Hlasko),  or  if  the  respiratory  centre 
be  inhibited  by  apnoea  (Grimm,  Grewe) — prevents  successful  vomiting,  as  does 
also  the  prevention  of  the  reflex  by  which  the  cardia  is  opened.  According  to 
Valenti,  the  opening  of  the  cardia  in  vomiting  may  be  brought  about  only  reflexly 
as  a  result  of  the  gastric  and  oesophageal  movements,  and  never  directly  by  central 
action.  The  centripetal  fibres  for  this  reflex  run  in  the  glossopharyngeal  and 
vagus  nerves,  and  may,  at  least  in  the  dog,  be  so  effectively  put  out  of  function 
by  cocainization  of  the  pharynx  and  upper  O3sophagus  that  the  stomach  is  not 
emptied,  in  spite  of  all  the  other  movements  of  vomiting. 

The  vomiting  centre  may  be  directly  stimulated  mechanically  as  by  the 
pressure  of  tumors  or  meningeal  inflammation,  or  chemically  as  in  uraemia, 
or  by  various  drugs  or  poisons,  or  by  disturbances  of  the  circulation  in  the 
brain.  It  may  also  be  stimulated  indirectly  or  reflexly  by  various  stimifli, 
among  which  are  psychical  ones,  such  as  disgust,  or  by  labyrinthine  disturbances, 
or  by  irritation  of  the  pharynx  or  of  abdominal  organs.  The  centripetal  impulses 
from  the  abdominal  organs  to  the  medullary  vomiting  centre  pass  upward  in 
the  vagi,  for,  after  their  division,  vomiting  can  no  longer  be  induced  by  influences 
acting  on  the  stomach  or  intestine. 

The  solipedes,  ruminators,  rodents,  and  chiroptera  (bats)  cannot  vomit, 
as  they  do  not  possess  the  necessary  coordinating  mechanism.  If  the  pathologi- 
cally dilated  fundus  be  overfilled,  vomiting  is  generally  difficult,  but  in  the  less 
developed  fundus  of  small  children  it  is  facilitated,  because  simple  contraction  of 
nie  antrum  of  the  pylorus  unassisted  by  the  pressure  of  the  abdominal  muscles 
is  sufficient  for  the  expulsion  of  the  stomach  contents  because  the  tone  of  the 
cardia  is  so  weak  (Valenti). 

12 


178  PHARMACOLOGY  OF  THE  DIGESTION 

Narcosis  of  the  Emetic  Centre. — In  deep  narcosis,  such  as  that 
caused  by  morphine,  chloral,  etc.,  the  vomiting  mechanism  does  not 
act  (Harnack),  and  consequently  under  such  conditions  the  emptying 
of  the  stomach  may  often  be  attained  only  by  the  use  of  the  stomach- 
tube. 

BIBLIOGRAPHY 

Grewe:   Berl.  klin.  Woch.,  1874. 

Grimm:    Pfliiger's  Arch.,  1871,  vol.  4. 

Hlasko:  Diss.,  Dorpat,  1887. 

Thumas:  Virchow's  Arch.,  vol.  123,  1891. 

Valenti:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  119. 

EMETICS 

All  substances  which,  by  their  powerful  action  on  the  mucous 
membrane  of  the  stomach  or  intestine,  cause  irritation,  inflammation, 
or  corrosion,  may  cause  vomiting.  Consequently,  vomiting  is  a  very 
common  symptom  in  almost  all  poisonings,  and  thus  forms  one  of 
the  most  important  reactions  by  which  the  organism  protects  itself. 
As  emetics  in  the  more  limited  pharmacological  sense,  however,  we 
speak  of  and  use  only  substances  which  cause  vomiting  as  their 
primary,  effect  without,  for  the  time  being,  appreciably  affecting  other 
organs  than  those  which  participate  in  the  act  of  vomiting.  One  can 
differentiate  between 

1.  Direct  emetics,  which  excite  the  vomiting  centre  directly,  and 

2.  Reflex  emetics,  which  act  by  irritating  those  specific  sensory 
nerve-endings,  in  the  mucous  membrane  of  the  stomach  and  intestine, 
the  excitation  of  which  induces  vomiting. 

We  are  forced  to  assume  the  presence  in  the  intestinal  mucous  membrane 
of  specific  "  emetico-sensory "  nerve-endings,  because  these  react  to  certain 
stimuli  such  as  marked  distention  and  to  certain  chemical  reagents,  but  not  to 
other  even  violent  stimuli  which  cause  pain  or  excite  secretion  or  normal  peri- 
staltic movements.  As  is  well  known,  a  similar  differentiation  is  found  in  the 
cutaneous  nerve-endings  through  which  stimuli  are  excited. 

Vomiting,  however  induced,  is  always,  except  in  small  children, 
preceded  by  a  prodromal  stage  of  nausea,  which  is  accompanied  by 
pallor,  cold  sweats,  increased  secretion  from  the  salivary  glands  and 
from  the  nasal  and  bronchial  mucous  membranes.  A  feeling  of  nausea 
and  often  marked  muscular  weakness  develops,  and  at  the  same  time 
the  pulse  becomes  somewhat  weaker  and  more  rapid  and  the  breathing 
rapid  and  irregular.  As  a  rule,  after  the  stomach  has  been  emptied 
and  vomiting  has  ceased,  all  these  symptoms  disappear,  except  that 
traces  of  the  muscular  weakness  remain  (Ackermann) .  It  is  thus 
apparent  that  stimulation  of  the  vomiting  centre,  even  before  it  has 
attained  the  threshold  value  for  emesis,  causes  an  accompanying  excita- 
tion of  a  whole  group  of  phenomena,  among  which  the  inhibition  of 
voluntary  movement  is  particularly  remarkable,  and  at  times  is  so 
extreme  that  it  completely  paralyzes  and  renders  apathetic  the  affected 


CENTRALLY  ACTING  EMETICS  179 

individual   so   that   his   condition   resembles   that   of   severe   shock 
(Harnack). 

The  slight  degrees  of  nausea,  which  express  themselves  only  in  aug- 
mentation of  the  secretions  and  perhaps  in  a  diminution  of  the  tone 
of  the  bronchial  muscles,  are  utilized  therapeutically  to  facilitate  the 
expectoration  of  tenacious  mucus  from  the  bronchi.  In  this  way  the 
emetics  in  non-emetic  doses  may  act  as  expectorants  (see  p.  343  ff.). 

CENTRALLY  ACTING  OR  DIRECT  EMETICS 

APOMORPHINE. — The  hydrochlorate  of  apomorphine,  a  base  obtained 
by  allowing  mineral  acids  to  act  upon  morphine  (Mathiesen  u. 
Wright],  when  injected  subcutaneously  in  doses  of  5-10  mg.,*  after 
5-10  minutes,  causes  nausea  and  vomiting,  which  is  repeated  two  or 
three  times,  after  which  the  patient  completely  recovers  from  these 
symptoms.  If  larger  amounts  be  administered,  the  vomiting  occurs 
repeatedly  for  an  hour  or  longer,  and  is  followed  by  a  condition  of 
moderate  weakness  and  somnolence  which  usually  soon  passes  off. 
When  taken  by  mouth,  apomorphine  acts  much  less  energetically,  10-20 
times  as  large  a  dose  being  necessary  and  the  vomiting  occurring  only 
after  half  an  hour  or  even  later.  From  this  it  may  be  concluded 
that  the  vomiting  caused  by  apomorphine  is  not  induced  reflexly  from 
the  mucous  membrane  of  the  stomach  and  intestine,  but  results  from 
direct  action  on  the  vomiting  centre  after  the  drug  has  been  carried 
there  in  the  blood. 

This  is  in  accordance  with  the  fact  that  even  after  section  of  both  vagi, 
in  which  lie  the  centripetal  nerves  running  from  the  stomach  and  intestine  to  the 
vomiting  centre,  apomorphine  causes  nausea  and  coordinated  vomiting  move- 
ments, which,  however,  on  account  of  the  disturbance  in  the  motor  innervation 
of  the  stomach,  do  not  always  actually  cause  emesis  (Grewe).  There  is  no 
ground  for  the  assumption  that  apomorphine  also  excites  antiperistaltic  move- 
ments of  the  stomach  by  direct  excitation  of  the  autonomic  centres  in  or  near 
the  stomach.  The  phenomena  observed  by  Schiitz  in  stomachs  removed  from 
dogs  previously  poisoned  by  apomorphine  or  other  emetics,  which  have  been 
held  to  speak  for  this  assumption,  are  to  be  looked  upon  as  merely  typical 
reversed  peristalsis  occurring  occasionally,  which,  even  without  the  influence 
of  any  drug,  may  also  be  caused  by  anaemia  of  the  stomach  and  which  were 
repeatedly  observed  by  Schiitz  himself  in  the  unpoisoned  isolated  stomach 
(Frantzen). 

As  has  already  been  mentioned,  stimulation  of  the  vomiting  centre, 
even  when  vomiting  does  not  occur,  induces  associatively  the  symptom 
complex  of  nausea,  and  if  this  centre  is  directly  excited  by  chemical 
means — as,  for  example,  by  apomorphine — or  as  a  result  of  cerebral 
anaemia,  it  is  clear  that  this  associative  accompanying  nausea  may 
be  more  pronounced  and  persistent  than  when  the  centre  is  temporarily 
excited  by  reflexes  from  the  stomach  or  intestine. 

*  In  dogs  as  small  doses  as  1.0-2.0  mg.  are  effective,  but  in  cats  10.0-30.0  mg. 
must  be  given,  and  in  many  of  these  animals  apomorphine  is  entirely  unable  to 
induce  vomiting. 


180  PHARMACOLOGY  OF  THE  DIGESTION 

Vomiting  entirely  fails  to  occur  or  is  only  partially  accomplished  if  one 
of  the  coordinating  mechanisms  involved  in  the  act,  perhaps  that  in  the  corpora 
quadrigemina,  for  some  reason  fails  to  act.  In  such  case  nausea  can  persist  for 
a  long  time  and  be  in  the  highest  degree  a  source  of  suffering,  and  the  motor 
inhibition  and  helplessness,  particularly  after  large  but  ineffective  doses  of 
apomorphine,  may  be  very  alarming.  In  rather  exceptional  cases  such  a  condi- 
tion may  persist  with  unabated  severity  for  some  time  even  after  vomiting  has 
occurred  ( Harnack ) ,  but  in  such-  cases  this  is  not  succeeded  by  other  harmful 
results.  Even  infants  of  but  a  few  months  old  can  support  without  harm  injec- 
tions of  %-1.0  mg.  of  apomorphine  (Jurasz).  Habituation  does  not  follow  its 
repeated  administration,  Siebert  having  for  4  weeks  injected  a  dog  each  day 
with  %-2.0  mg.  of  apomorphine,  each  injection  being  followed  after  about  three 
minutes  by  vomiting.  However,  many  commercial  preparations  of  apomorphine 
are  contaminated  by  a  percentage  of  chloromorphid,  a  toxic  respiratory  depres- 
sant, which  is  probably  the  explanation  for  some  of  the  cases  of  poisoning  which 
have  followed  the  medicinal  administration  of  apomorphine  (Harnack  u. 
Hildebrandt ) . 

Other  Actions. — The  vomiting  centre  and  its  coordinately  controlled 
central  mechanisms  form  the  predilective,  but  not  the  only  point  on 
which  apomorphine  acts. 

In  dogs  in  large  doses  (0.06-0.1  gm.),  and  in  cats  even  in  emetic  doses 
(0.02-0.05  gm.),  it  causes  a  condition  of  marked  excitement  and  confusion,  with 
accelerated  respiration  and  active  forced  movements.  In  rabbits  and  guinea- 
pigs  also  ita  administration  is  followed  by  great  restlessness  and  timidity  and 
an  irresistible  tendency  to  gnawing,  and  after  doses  of  more  than  10  mg.  con- 
vulsions resulting  in  death  occur.  Hogs,  which  normally  can  vomit,  cannot  be 
caused  to  vomit  by  apomorphine,  but  after  the  subcutaneous  injection  of  0.02- 
0.5  mg.  they  become  highly  excited  and  gnaw  and  bore  in  the  floor  and  walls 
of  their  pens.  Similar  remarkable  symptoms  of  excitement,  an  irresistible  desire 
to  lick  and  gnaw,  are  also  produced  by  apomorphine  in  cattle  and  horses,  and 
even  chickens  and  doves  -are  rendered  restless  by  it  and  peck  continually  on 
the  floor  and  at  their  own  claws  but  do  not  vomit  (Feser). 

OTHER  CENTRAL  EMETICS. — Many  other  substances  directly  stimu- 
late the  vomiting  and  the  respiratory  centres  in  a  manner  similar 
to  apomorphine.  Their  actions,  however,  are  not  so  elective,  but  ex- 
tend usually  to  other  functions,  and  consequently  they  are  not  suit- 
able for  the  isolated  induction  of  emesis.  In  this  group  belong  aspi- 
dosamine,  an  alkaloid  of  the  quebracho  bark  (Harnack  u.  Hoffmann), 
and  lobeline,  an  alkaloid  of  Lobelia  inflata,  which  formerly  was  used 
as  an  emetic,  but  now  is  used  only  in  small  non-emetic  and  safe  doses 
in  the  treatment  of  asthma  (seep.  345).  Probably  verair'me,  the  active 
principle  of  Veratrum  sabadilla  and  Veratrum  viride,  should  also  be 
placed  in  this  group,  for  in  addition  to  many  other  characteristic 
actions,  particularly  on  striped  muscles,  it  causes  vomiting  by  a 
central  action.  Administered  subcutaneously  it  is  a  very  effective 
emetic  in  hogs  and  for  this  purpose  it  is  used  by  veterinarians. 

Morphine  also,  by  a  probably  direct  action  on  the  vomiting  centre, 
induces  vomiting  in  dogs  and,  as  a  late  effect,  quite  often  in  man. 

BIBLIOGRAPHY 

Ackermann:  Beob.  iiber  einige  physiol.  Wirkungen  d.  Emetica,  Rostock,  1856. 
Feser:   Ztschr.  f.  pr.  Veterinarwiss,  1873-75. 
Frant/pn  :     Diss..  Doroat.  1887. 


jtJBcr:    ^i/Bciii.  i.  pi.    v  cue i umi  w 
Frantzen:    Diss.,  Dorpat,  1887. 


PERIPHERAL  EMETICS  181 

Grewe:  Diss.,  Dorpat,  1874. 

Grewe:   Berl.  klin.  Woch.,  1874,  vol..  11. 

Harnack:   MUnchn.  med.  Woch.,  1908,  No.  36. 

Harnack  u.  Hildebrandt:    Miinchn.  med.  Woch.,  1910,  Nos.  1  and  33. 

Harnack  u.  Hildebrandt:   Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  65,  p.  38. 

Harnack  u.  Hoffmann:    Ztschr.  f.  klin.  Med.,  1885,  vol.  8. 

Jurasz:   Deut.  Arch.  f.  klin.  Med.,  1875,  vol.  16. 

Mathiesen  u.  Wright:   Liebig's  Ann.  Suppl.,  1869,  vol.  7. 

Schiitz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1886,  vol.  21. 

Siebert:  Diss.,  Dorpat,  1871. 

EMETICS  ACTING  PERIPHERALLY  OR  REFLEXLY 

IPECAC,  Radix  ipecacuanhas,  contains  about  2  per  cent,  of  a  mixture 
of  the  alkaloids,  emetine  and  cephaeline,  and  also  an  acid  resembling 
tannin.  While  both  of  these  alkaloids  are  emetics  and  cephaeline  is 
the  more  powerful  one,  only  emetine  has  been  exactly  studied  pharma- 
cologically. It  possesses  a  bitter  and  irritating  taste  and  violently 
irritates  the  mucous  membranes,  causing  in  them  inflammation  with 
paralysis  of  the  capillaries.  Consequently,  when  administered  in  suffi- 
cient amounts,  it  causes  in  animals  not  only  vomiting  but  also  violent 
and  at  times  bloody  diarrhcea  resembling  that  caused  by  colchicine  and 
arsenical  or  antimonial  compounds,  to  the  effects  of  which  emetine 
poisoning  in  many  particulars  corresponds  exactly. 

As  the  emetic  effects  occur  no  more  rapidly  and  are  not  produced  by 
smaller  amounts  when  this  drug  is  injected  subcutaneously  or  intravenously  than 
when  it  is  introduced  into  the  stomach,  it  may  be  concluded  that  it  acts  reflexly 
on  the  gastric  mucous  membrane.  The  fact  that,  even  after  subcutaneous  injec- 
tion, it  reaches  the  gastric  and  intestinal  mucous  membrane  is  evidenced  by  the 
inflammation  of  the  intestinal  mucous  membrane  and  by  the  identification  of 
emetine  in  the  intestinal  contents  (D'Ornellas). 

On  the  other  hand,  Thurnas  states  that  a  solution  of  emetine  applied 
directly  to  the  vomiting  centre  in  the  medulla  quickly  induces  vomiting,  and 
consequently  he  looks  upon  it  as  an  emetic  which  acts  directly  on  this  centre. 
However,  in  view  of  the  general  irritating  effects  of  emetine,  his  results  permit 
of  more  than  one  interpretation.  After  elimination  of  the  centripetal  vagus 
fibres,  vomiting  was  not  caused  by  it  in  Duckworth's  and  Polichromie's  experi- 
ments, while  in  those  of  D'Ornellas  they  occurred  in  some  cases  but  only  very 
late  and  to  a  very  slight  extent. 

These  observations  indicate  that  it  acts  reflexly  and  not  directly. 
In  man  10.0-15.0  mg.  of  emetine  cause  nausea  and  after  %-l  hour 
vomiting,  but,  on  account  of  the  difficulty  with  which  this  drug  may 
)e  preserved,  it  is  not  suitable  for  general  use  at  the  present.     As 
ilenic  preparations  of  ipecac  contain  the  emetine  only  in  colloidal 
)mbination,  they  never  cause  marked  irritation  of  the  intestine,*  but, 
should  be  expected  from  their  very  slow  absorption,  only  persistent 
lausea,  and  after  a  sufficient  dose  (for  adults  1.0-2.0  gm.)  vomiting 

[The  large  doses  employed  in  the  treatment  of  dysentery  not  infre- 
lently  cause  considerable  irritation  of  the  intestinal  mucous  membrane,  and 
Dnsequently  may  aggravate  or  cause  dysenteric  symptoms,  a  fact  which  should 
lot  be  forgotten  when  the  drug  is  employed  in  such  cases,  otherwise  its  adminis- 
ration  may  at  times  be  continued  after  it  has  accomplished  the  desired  effect  on 
ie  amoebae. — TR.] 


182  PHARMACOLOGY  OF  THE  DIGESTION 

in  the  course  of  %-l  hour.  On  account  of  its  slow  action,  ipecac  is 
not  much  used  as  an  emetic  but  chiefly  as  an  expectorant. 

In  its  original  home  this  drug  has  been  employed  for  centuries 
not  only  as  an  emetic  but  also  as  a  specific  in  dysentery,  being  used  for 
this  purpose  in  the  form  of  a  concentrated  decoction.*  After  repeated 
doses  it  ceases  to  cause  vomiting  and  its  curative  action  in  the  intestine 
manifests  itself.  Probably  the  effective  factor  in  these  cases  is  essen- 
tially the  astringent  ipecacuaha-tannic  acid  (see  Astringents)  .t  Conse- 
quently "emetine-free"  ipecac  preparations  have  been  prepared  and 
recommended  for  the  treatment  of  dysentery,  but  it  is  doubtful  whether 
these  possess  any  advantage  over  any  other  preparation  containing 
tannin.  [There  can  be  no  doubt  that  such  preparations  are  useless 
in  amo3bic  dysentery. — TR.] 

COPPER  SULPHATE  in  doses  of  0.1-0.2  gm.  (maximum  dose  1.0  gm.), 
introduced  in  dilute  solution  into  the  stomach,  after  a  few  minutes 
causes  emesis  and  nausea  which  last  for  only  a  very  short  time.  If 
the  vagi  have  been  divided  in  animals  so  that  the  reflex  action  through 
the  stomach  is  prevented,  copper  sulphate  causes  no  vomiting. 

Reputed  Toxic  Action. — Under  ordinary  conditions  the  rapid  ex- 
pulsion of  the  stomach  contents  keeps  this  salt  from  damaging  the 
mucous  membrane  to  any  appreciable  extent,  but,  even  if  it  does  pass 
into  the  intestine  with  the  stomach  contents,  it  is  absorbed  very  slowly 
and  in  very  small  amounts.  Consequently  harmful  effects-  due  to  its 
action  after  absorption  are  unknown,  even  when  for  months  small 
doses  have  been  administered  daily  (Toussaint,  Burget,  Lehmann). 
The  supposed  poisonous  character  of  acid  foods  which  have  stood  in 
copper  vessels  is  almost  certainly  not  due  to  their  containing  salts  of 
copper.  For  these  various  reasons  copper  sulphate  may  be  stated  to 
be  a  relatively  safe  drug,  which  can  produce  a  severe  gastro-enteritis 
only  in  case  exceedingly  large  doses,  amounting  to  several  grammes, 
be  administered  at  one  time,  in  which  case  it  is  also  possible  that  sys- 
temic poisoning  could  result.  [The  prohibition  of  copper  as  a  color- 
ing agent  for  foods  is  not  justifiable  from  a  hygienic  standpoint. — TR.] 

In  molluscs  copper  and  zinc  also  occur  in  considerable  amounts  as  normal 
organically  combined  constituents  of  the  protoplasm  ( Mendel  and  Bradley ) . 
Plants,  too,  absorb  considerable  amounts  of  copper  from  soils  containing  it  with- 
out disturbance  of  their  growth,  and  in  fact  under  some  conditions  apparently 
with  beneficial  effects.  When  copper  in  the  form  of  copper  alkali-album inate 
or  tartarate,  which  do  not  coagulate  proteid,  is  injected  subcutaneously  or  intra- 
venously for  the  purpose  of  causing  a  systemic  intoxication,  even  small  amounts 

*  [In  dysentery  ipecac  is  best  administered  in  salol-coated  pills,  each  con- 
taining 0.3-4  gm.  of  the  finely  powdered  root. — TR.] 

t[With  the  above  view  of  the  method  of  action  of  ipecac  in  amoebic  dysen- 
tery few  who  have  had  experience  with  this  disease  will  agree.  The  translator, 
like  many  others,  is  convinced  that  ipecac  properly  employed  is  the  most  effective 
curative  agent  that  we  possess  for  amoebic  dysentery.  Recent  clinical  experiences 
with  emetine  hydrochloride  administered  subcutaneously  speak  very  strongly 
for  the  assumption  that  emetine  is  the  efficient  curative  agent  in  such  cases. — TR.] 


PERIPHERAL  EMETICS  183 

exert  a  paralytic  action  on  the  central  nervous  system  as  well  as  on  the  striped 
muscles,  and  cause  manifold  degenerations  of  the  tissues,  particularly  in  those 
of  the  kidney,  while  in  larger  doses  it  kills  by  acute  paralysis  ( E.  Harnack ) . 

Therapeutically  copper  sulphate  is  employed  as  a  rapid  and  cer- 
tainly acting  emetic,  but  it  is  hardly  possible  for  it  to  cause  a  persistent 
enough  mild  nausea  for  it  to  act  as  an  expectorant.  At  the  present 
time  it  is  not  possible  to  formulate  any  indications  for  its  administra- 
tion with  the  idea  of  its  acting  after  absorption.  It  is,  however,  of 
particular  value  as  the  antidote  in  acute  phosphorus  poisoning  [as  it 
acts  not  only  as  an  emetic  but  also  as  a  chemical  antidote. — TR.] 

ZINC  SULPHATE  has  the  same  emetic  action  as  copper  sulphate.  The 
medicinal  dose  is  1.0  gm.  per  dose  and  per  diem.  The  fact  that  nowa- 
days it  is  seldom  used  as  an  emetic  is  difficult  to  understand,  particu- 
larly as  the  danger  of  zinc  poisoning  is  quite  as  slight  as  that  of 
copper  poisoning.  Just  as  copper  is  present  in  preserved  vegetables 
and  fruits  colored  green  with  copper,  considerable  amounts  of  zinc  are 
present  in  fruits  dried  in  zinc  trays,  but  harmful  results  due  to  the  use 
of  such  dried  fruits  are  unknown.  The  same  is  true  of  the  effects 
of  the  long-continued  administration  of  non-corrosive  zinc  compounds, 
even  though  zinc  is  slowly  absorbed  and  stored  up  in  all  the  organs 
of  the  body. 

According  to  Javillier,  zinc,  like  iron  and  manganese,  is  a  regular  con- 
stituent of  vegetable  protoplasm.  When  present  in  very  slight  concentration,  it 
stimulates  the  growth  of  yeast  and  also  of  grains. 

Zinc  compounds,  particularly  zinc  oxide,  were  formerly  employed 
as  supposedly  curative  agents  in  chorea,  epilepsy,  and  other  nervous 
diseases.  From  the  few  facts  known  to  us  of  the  manner  in  which  zinc 
acts,  as  learned  from  pathological  experiments,  it  is  not  possible  to 
form  any  opinion  as  to  the  possibility  of  zinc's  exerting  any  curative 
action  in  such  diseases. 

TARTAR  EMETIC,  antimony  and  potassium  tartrate,  like  all  other 
soluble  antimonial  compounds,  introduced  into  the  stomach  or  intes- 
tine, reflexly  causes  decided  nausea  and,  as  a  rule,  but  not  always, 
vomiting. 

Toxic  Actions. — At  the  same  time  this  salt,  depending  on  the  length 
of  time  that  it  remains  in  the  alimentary  canal,  produces  a  more  or 
less  deep  and  extensive  corrosion  of  the  epithelium  of  the  mucous 
membranes,  and  thus  opens  the  path  for  its  absorption  into  the  blood 
and  lymph-vessels.  Moreover,  even  when  the  gastric  and  intestinal 
mucous  membranes  remain  uninjured,  antimony  may  be  absorbed  and 
cause  a  systemic  poisoning,  which  in  all  essential  particulars  resembles 
that  caused  by  arsenic.  This  consists  in  general  paralysis  of  the  capil- 
laries (Schmiedeberg),  weakening  of  the  heart's  action,  and  extensive 
exfoliative  enteritis,  which  is  due  in  part  to  an  abnormal  transudation 
into  the  villi  resulting  from  the  paralysis  of  their  capillaries  and  in 


184 

part  to  the  direct  cytotoxic  effect  of  the  antimony,  which  is  re-excreted 
through  these  mucous  membranes.  In  addition  there  is  paralysis  of 
the  central  nervous  system,  with  increasing  apathy  and  motor  paralysis. 

These  actions  render  the  soluble  antimony  salts  extremely  danger- 
ous poisons,  which  are  all  the  more  dangerous  because  occasionally 
vomiting  fails  to  occur,  so  that  quite  large  amounts  of  antimony 
may  be  absorbed.  The  administration  of  0.2  gm.  of  tartar  emetic  in 
solution  has  more  than  once  caused  death  in  adult  human  beings 
(Taylor}.  It  should  consequently  be  the  rule,  in  case  this  drug  be 
used  at  all  as  an  emetic,  that  if  vomiting  does  not  follow  within  an 
hour  its  administration  should  be  followed  by  a  dose  of  tannic  acid, 
which  renders  this  poison  insoluble  in  the  alimentary  canal  and  thus 
interferes  with  its  action.  In  the  German  and  Austrian  pharmaco- 
poeias, the  maximal  dose  of  0.2  gm.  per  dose,  0.5  gm.  per  diem,  has 
been  reduced  to  0.1  gm.  and  0.3  gm. 

As  an  Expectorant. — Tartar  emetic  is  not  at  all  suitable  for  the 
purpose  of  producing  simply  persistent  nausea  (expectoration),  but 
if  any  preparation  of  antimony  is  to  be  used  for  this  indication  it 
should  be  the  insoluble  sulphide  of  antimony  Sb2S5,  only  small  amounts 
of  which  are  dissolved  by  the  acids  of  the  stomach. 

Externally  tartar  emetic,  applied  in  concentrated  solution  or  rubbed  in  as 
a  salve,  causes  after  some  time  burning  and  inflammation  and  the  formation 
of  pustules  entirely  similar  to  those  of  variola.  Moderately  severe  dermatitis 
has  occasionally  resulted  from  the  wearing  of  clothes  the  materials  of  which 
contained  antimony  ( Lehmann  u.  Gobel ) .  While  formerly  much  used  as  a  deriva- 
tive, the  use  of  such  salves  has  been  correctly  abandoned. 

Systemic  Actions. — To-day,  except  in  the  treatment  of  psoriasis  of 
long  standing  (Boeck  u.  Danielsen),  hardly  ever  is  use  made  of 
the  chronic  systemic  actions  of  small  doses  of  antimony,  which  are 
the  same  as  those  of  arsenic,  expressing  themselves  in  similar  altera- 
tions of  the  metabolism,  the  anabolism  and  catabolism  of  the  tissues. 
This  is  probably  due  to  the  fact  that  they  cannot  be  obtained  with 
so  little  disturbance  as  by  arsenic,  for  the  soluble  arsenical  compounds 
are  readily  absorbed  and  consequently  do  not  remain  in  the  alimen- 
tary canal  long  enough  to  cause  any  irritation,  while  the  antimony 
salts  are  absorbed  so  slowly  that  they  are  very  apt  to  cause  nausea 
and  vomiting  and  even  severe  damage  to  the  tissues.*  In  all  proba- 
bility it  should  be  possible  with  suitable  organic  antimonial  compounds 
to  obtain  all  the  therapeutic  effects  of  arsenic,  including  the  etiotropic 
ones  (see  Atoxyl,  etc.). 

BIBLIOGRAPHY 

Bohm  u.  Unterberger:  Arch.  f.  exp.  Path.  u.  Pharm.,  1874,  vol.  2. 
Burget,  Ducon  et  Galippe:  Arch,  de  Phys.,  1887,  vol.  4. 
D'Ornellas:   Bull.  mgd.  d.  1.  Soc.  de  Thgr.,  1873. 

*  Radziejewski  (Dubois'  Arch.,  1871)  after  the  administration  of  0.12  gm. 
of  tartar  emetic  recovered  0.11  gm.  from  the  vomited  material. 


EMESIS  185 

Duckworth:   St.  Barthol.  Hosp.  Rep.,  1869-1871. 

Harnack,  E.:   Arch.  f.  exp.  Path.  u.  Pharm.,  1874,  vol.  3. 

Javillier:    Bull.  Science  pharmacol.,  1908,  vol.  15,  p.  129. 

Lehmann:    Arch.  f.  Hygien.,  1898,  vol.  31,  literature. 

Lehmann  u.  Gobel:   Arch.  f.  Hygien.,  vol.  43. 

Mendel  and  Bradley:  Am.  Journ.  of  Phys.,  1905,  vol.  14. 

Polichromie:   These  de  Paris,  1874. 

Radziejewski :   Dubois'  Archiv,  1871. 

Taylor:  Die  Gifte.  Deutsch  von  Seydeler,  1863. 

Toussaint:   1857,  Vierteljahrschr.  f.  ger.  Med.,  vol.  12. 

Wild:   Lancet,  1895. 

Emesis  as  an  undesirable  side  action  often  results  from  the  spas- 
modic contractions  of  the  gastric  and  intestinal  muscles  caused  by 
poisonous  doses  of  lead,  barium,  fly-agaric  (poisonous  mushrooms), 
and  tobacco,  as  also  not  infrequently  when  pilocarpirie  is  adminis- 
tered medicinally.  The  vomiting  which  occurs  after  small  doses  of 
morphine  almost  always  in  dogs,  and  not  infrequently  in  man,  is  prob- 
ably due  not  only  to  a  central  action  (see  p.  34)  but  also  to  a  reflex 
which  is  excited  by  the  spasm  of  the  sphincter  of  the  pylorus  produced 
by  morphine  (Magnus]  (p.  189). 

TREATMENT  OF  VOMITING 

The  vomiting  caused  by  morphine  may  often  be  prevented  or 
relieved  by  small  doses  of  atropine  (G'uinard),  which  diminishes 
or  relieves  the  spasm  of  the  sphincters  of  the  antrum  of  the  pylorus 
and  of  the  pylorus  itself  (Meltzer  and  Auer).  The  vomiting  caused 
by  pilocarpine  is  also  relieved  by  small  doses  of  the  antagonistically 
acting  atropine,  which,  however,  to  a  greater  or  less  degree  inhibits 
the  other  actions  of  pilocarpine. 

Just  as  the  algesic  nerve-endings  in  the  skin,  and  those  in  the 
mucous  membranes,  the  peritoneum,  and  probably  everywhere  in  the 
body,  may  as  a  result  of  inflammation  become  hypersusceptible  to  an 
extreme  degree,  and  may  in  such  cases  react  to  stimuli  which  ordinarily 
are  ineffective,  so,  too,  the  specific  nerve-endings  in  the  pharynx  and  in 
the  abdominal  organs,  through  which  the  vomiting  reflex  is  excited, 

ay  also  become  hyperexcitable  when  these  tissues  become  inflamed, 
that  vomiting  may  occur  spontaneously  or  as  the  result  of  any  irri- 

,tion  which  may  be  present.    Examples  of  vomiting  thus  induced  are 

.e  vomiting  in  gastritis,  gall-stone  colic,  strangulation  of  the  intes- 
es,  etc.     In  such  cases  excessive  and  distressing  vomiting  may  be 

ilieved  by  lessening  the  irritation  or  by  narcotizing  the  irritated 
regions  by  means  of  cocaine,  orthoform,  etc.,  or  by  cold, — for  example, 
by  swallowing  pieces  of  ice.  When  vomiting  is  due  to  other  causes 
less  well  understood, — for  example,  the  hyperemesis  of  pregnancy,  sea- 
sickness, etc., — we  must  endeavor  to  relieve  it  by  narcotizing  the 

uniting  centre  by  large  doses  of  morphine  with  %  mg.  of  scopo- 
ine  administered  subcutaneously,  or  by  the  rectal  administration 


186  PHARMACOLOGY  OF  THE  DIGESTION 

of  chloral  and  by  other  similar  procedures.  Possibly  the  application 
of  ice  to  the  back  of  the  neck,  which  is  occasionally  effective,  acts  in 
a  similar  fashion. 

BIBLIOGRAPHY 

Guinard:   Lyon  med.,  1895,  vol.  27,  Nos.  35  and  36. 
Magnus:   Pfliiger's  Arch.,   1908,  vol.   122. 
Meltzer  u.  Auer:   Am.  Journ.  of  Physiol.,  1906. 

NORMAL  MOVEMENTS   OF  THE  STOMACH 

By  the  normal  movements  of  the  stomach  solid  and  liquid  foods  arc 
churned  about  in  the  fundus,  in  which  the  hydrochloric  acid  and  much  the  largest 
part  of  the  pepsin  is  secreted,  and  are  permitted  to  pass  gradually  in  a  par- 
tially digested  condition  into  the  antruni  of  the  pylorus,  from  which,  after 
further  preparation,  they  are  shoved  along  little  by  little  into  the  duodenum. 
This  gradual  movement  of  the  stomach  contents  is  controlled  by  three  sphincters, 
the  cardia,  the  sphincter  antri  pylori,  and  the  sphincter  pylori.  The  first  two 
of  these  close  the  fundus  off  from  the  oesophagus  and  from  the  antrum,  so  as  to 
permit  it  to  act  without  interference,  while  the  sphincter  of  the  pylorus  sees  to 
it  that  the  properly  prepared  and  acidified  chyme  passes  in  properly  measured 
portions  into  the  duodenum,  where  it  is  further  modified  and  passed  along. 

As,  like  every  other  ferment  reaction,  the  hydrochloric  acid-pepsin  diges- 
tion is  very  markedly  retarded  by  dilution  with  water,  a  provision  is  made  to 
prevent  the  admixture  of  fluids  with  the  contents  of  the  fundus  and  to  allow 
them  to  pass  along  into  the  antruni  in  a  sort  of  muscular  trough,  which  runs 
along  the  small  curvature  above  the  fundus  and  its  contents  (Kaufmann,  Cohn- 
lieim ) . 

When  the  stomach  is  filled,  active  but  not  very  extensive  peristaltic  move- 
ments of  the  fundus  occur,  by  means  of  which  its  contents  are  brought  into 
contact  with  the  gastric  juice  as  it  exudes  from  the  mucous  membrane.  For 
the  performance  of  this  function  the  fundus  constantly  accommodates  itself 
to  its  contents,  dilating  reflexly  without  any  increase  of  tension  pressure  as  it 
grows  fuller,  and  contracting  again  as  its  contents  pass  into  the  antrum 
(Sick  u.  Tedesko) ,  the  fundus  behaving  here  similarly  to  the  bladder.  If  as 
a  result  of  sudden  overfilling  of  the  fundus  the  pressure  within  it  rises  to 
about  25  cm.  of  water,  the  cardia  opens  so  that  regurgitation  or  vomiting  may 
occur  (Kelling).  In  the  antrum  of  the  pylorus  the  peristalsis  is  much  more 
active,  and  is  powerful  enough  to  mix  its  contents  thoroughly  and  to  force  it 
out  through  the  pylorus. 

Innervation. — The  reflex  coordinating  mechanism  for  these  peristaltic  move- 
ments of  the  stomach  is  situated  in  Auerbach's  plexus,  which  receives  stimu- 
lating impulses  through  the  vagus  and  inhibitory  impulses  from  the  sympathetic. 
In  a  similar  fashion  the  function  of  the  pyloric  and  cardial  sphincters  is  con- 
trolled by  ganglia  supplied  by  the  vagus  and  the  sympathetic  (Openchowski) . 
Division  of  both  the  vagi  and  the  sympathetics  is  not  followed  by  any  essential 
alteration  of  the  gastric  automatism  or  reflexes,  but  when  the  vagi  alone  are 
divided  the  unopposed  constant  inhibitory  effect  of  the  sympathetic  causes 
permanent  disturbance  of  the  gastric  motor  functions  (Cannon). 

The  normal  muscular  movements  of  the  stomach  may  also  be  reflexly 
stimulated  or  inhibited  in  a  reflex  manner  by  chemical  action  on  the  gastric 
mucous  membranes  or  by  a  direct  action  on  its  motor  nervous  mechanism. 

Such  reflexes  are  excited  normally  by  the  food  and  by  the  gastric  juice, 
the  hydrochloric  acid  of  which  furnishes  the  necessary  stimulation  for  the 
movements  of  the  stomach  (Edelmann).  Peristalsis  is  also  excited  by  carbon 
dioxide,  the  partial  pressure  of  which  in  the  fasting  stomach  amounts  to  30-50 
mm.  Hg,  but  which  during  digestion  may  rise  to  130-140  mm.  Hg  ( Schierbeck ) . 
This  effect  is  also  produced  when  beverages  containing  carbonic  acid  are  drunk 
or  when  sodium  bicarbonate  is  administered.  Those  peristaltic  movements  of  the 
antrum  of  the  pylorus  (by  which  the  food  is  expelled  into  the  duodenum)  and  the 
opening  of  the  pylorus  (which  cooperates  with  them)  are  consequently  seen  to  be  de- 
pendent on  the  normal  acid  reaction  of  the  stomach  contents,  an  alkaline  reaction 


GASTRIC  MOTILITY  187 

of  the  stomach  contents  leaving  the  pylorus  closed,  while  too  high  acidity  may 
cause  a  persistent  pyloric  spasm.  Otherwise  the  pyloric  peristalsis  is  governed 
almost  entirely  in  a  reflex  fashion  by  the  chemical  composition  of  the  duodenal 
contents,  alkalinity  exciting  the  emptying  mechanism  while  acidity  or  unsaponified 
fats  inhibit  it.  This  explains*  the  so-called  indigestibility  of  greasy  or  very  acid 
foods  such  as  unripe  fruits,  which  remain  for  a  long  time  in  the  stomach,  being 
able  to  leave  it  only  as  rapidly  as  they  are  absorbed  or  neutralized  in  the  small 
intestine  or  pass  along  into  the  colon. 

BIBLIOGRAPHY 

Cannon:   Zentralbl.  f.  Physiol.,  1906,  vol.  20. 

Cohnheim:   Miinchn.  med.  Woch.,  1907. 

Edelmann:  Diss.,   1906,  Petersburg,  russ.    (Maly,  1906). 

Kaufmann:   Ztschr.  f.  Heilk.,  1907,  vol.  28,  No.  7. 

Kelling:  Arch.  f.  klin.  Chir.,  1901,  vol.  64,  p.  393. 

Openchowski:   Zentralbl.  f.  Physiol.,   1889. 

Schierbeck:   Skand.  Arch.  f.  Physiol.,  1891,  vol.  3. 

Sick  u.  Tedesko:  Deut.  Arch.  f.  klin.  Med.,  1908,  vol.  92. 

INFLUENCE  EXERTED  BY  DRUGS  ON  GASTRIC  MOTILITY 

In  a  reflex  fashion  the  normal  peristalsis  of  the  stomach  may 
hardly  be  affected  by  drugs,  but  it  is  possible  that  the  BITTERS  stimu- 
late it  (Batelli,  Heubner). 

The  more  concentrated  solutions  of  NEUTRAL  SALTS  are,  the  more 
do  they  inhibit  the  movements1  of  the  stomach,  and  it  is  found  that 
magnesia  compounds  and  sugar  solutions  inhibit  it  to  a  greater  extent 
than  do  the  sodium  salts.  This  is  the  reason  why  only  those  mineral 
waters  which  contain  very  small  amounts  of  salts  are  used  as  table 
waters,  for  the  more  concentrated  ones  only  retard  the  emptying 
of  the  stomach  and  so  cause  discomfort.  For  the  same  reason,  during 
water-cures  the  stronger  mineral  waters  should  always  be  taken  when 
fasting  and  as  long  as  possible  before  eating.  The  temperature  of  the 
water  is  also  not  without  importance,  for  warm  drinks  are  passed 
along  through  the  stomach  more  rapidly  and  cold  ones  more  slowly 
(Dapper  u.  v.  Noorden}. 

The  motor  function  of  the  stomach  can  be  influenced  in  a  much 
more  effective  fashion  by  the  direct  action  of  "autonomic"  drugs. 

EXCITATION  BY  "  AUTONOMIC  "  DRUGS 

Poisoning  with  pilocarpine,  pliysostigmine,  and  nicotine  causes 
violent  atypical  gastric  peristalsis  and  readily  causes  reflex  vomiting. 

Choline,  (CHS)SNOH  C2H4O,  also  augments  the  vagus  tone  and  gastric 
peristalsis,  but  much  less  strongly  than  the  above-mentioned  drugs.  Neurin, 
(CH3)3NOHC2HS,  which  under  some  circumstances — for  example,  under  the 
influence  of  bacteria  (E.  Schmidt) — is  formed  from  choline,  is  a  powerful  ex- 
citant of  the  autonomic  organs.  As  choline  is  a  normal  constituent  of  the  body 
fluids  and  in  some  diseases  occurs  in  increased  amounts,  either  choline  or  the 
neurin  formed  from  it  may  possibly  be  the  cause  of  the  increased  activity  of  the 
movements  of  the  stomach  and  intestine.  It  is  possible  also  that  during  digestion 
it  is  produced  in  larger  amounts  than  during  fasting,  and  that  it  consequently 
causes  an  augmentation  of  the  tone  of  the  vagus,  which  apparently  is  necessary 
during  digestion. 


188  PHARMACOLOGY  OF  THE  DIGESTION 

In  this  connection  it  may  be  mentioned  that  a  number  of  other  drugs  excite 
gastric  and  intestinal  peristalsis,  particularly  ergotin  (Auer  u.  Meltzer)  and 
the  digitalis  glucosides,  and  that  consequently  the  gastric  function  may  be 
markedly  disturbed  by  the  medicinal  use  of  these  drugs. 

However,  the  indication  to  use  such  stimulating  drugs  for  the 
purpose  of  reviving  and  augmenting  gastric  peristalsis  does  not  exist 
practically,  for  in  simple  gastric  atony  a  temporary  strengthening  of 
the  gastric  peristalsis  lasting  about  an  hour  would  hardly  be  of  any 
benefit,  and  this  is  all  that  such  drugs  could  accomplish.  Strychnine 
is  often  prescribed  to  increase  the  tone  of  the  stomach,  but  there  is  no 
experimental  evidence  that  it  does  so  (Langley  and  Magnus,  Paderi). 

BIBLIOGRAPHY 

Auer  and  Meltzer:  Am.  Journ.  of  Physiol.,  1906,  vol.  17. 

Batelli:    Diss.,  Genf.,  1896. 

Dapper  u.  v.  Noorden:  Einfl.  d.  Mineralwasser  auf  d.  Stoffw.  in  Hdb.  d.  Pathol.  d. 

Stoffw.,  1907,  literature. 
Heubner:    Therap.  Monatsh.,  1909,  No.  6. 

Langley  and  Magnus:  Journ.  of  Physiol.,  1905-07,  vols.  33  and  36. 
Paderi:   La  Thfirapie  mod.,  1892,  No.  12. 
Schmidt,  E.:  Arch.  d.  Pharm.,  1891,  p.  481. 


ATROPINE  inhibits  the  contractions  of  the  gastric  muscles,  and  thus 
may  be  of  therapeutic  value  in  all  those  conditions  in  which  the 
indication  is  to  moderate  too  violent  gastric  peristalsis  or  in  any 
inflammatory  and  painful  conditions  of  the  stomach  wall.  For 
example,  in  gastric  ulcer  there  is  an  indication  for  quieting  the  stom- 
ach as  far  as  is  possible  and  of  relaxing  reflex  pyloric  spasm  (Schick*). 

Although  small  doses  (of  1.0-2.0  mg.)  by  no  means  paralyze  the 
motor  ganglia  of  the  gastric  Auerbach's  plexus,  they  do  depress  or 
paralyze  the  vagal  motor  nerve-endings  which  are  physiologically  con- 
nected with  it  (Auer  u.  Meltzer},  while  the  inhibitory  sympathetic 
nerve-endings  are  paralyzed  only  by  such  large  doses  as  are  never 
used  in  practice.  Consequently,  the  result  of  the  administration  of 
moderate  doses  is  that  the  inhibitory  impulses  gain  the  upper  hand 
and  the  stomach  is  quieted,  an  effect  which  is  the  more  striking  the 
more  pronounced  the  previous  stimulation  of  the  vagus  nerve-endings 
has  been, — for  example,  after  administration  of  pilocarpine  or  choline. 

In  those  conditions  in  which  the  activity  of  the  stomach  movements  is  due 
to  a  diminished  inhibitory  tonus,  less  effect  is  to  be  expected  from  atropine, 
and,  as  epinephrin  stimulates  the  sympathetic  nerve-endings  which  are  here 
inhibitory  organs,  this  drug  should  be  the  more  effective  gastric  sedative.  How- 
ever, this  is  at  present  only  of  theoretical  importance,  for  when  introduced  into 
the  stomach  or  administered  subcutaneously  epinephrin  is  entirely  ineffective 
and  even  when  injected  intravenously  acts  for  only  a  few  minutes. 

MORPHINE  produces  a  very  peculiar  effect  on  gastric  motility.  In 
dogs  with  duodenal  fistula  Hirsch  observed  that  the  emptying  of  the 
stomach  was  markedly  retarded  by  morphine.  Using  Cannon 's  X-ray 


GASTRIC  MOTILITY  189 

method,  in  which  the  food  is  mixed  with  bismuth  subnitrate  and  thus 
may  be  rendered  visible  on  the  fluoroscope,  Magnus  investigated  this 
phase  of  its  action  on  dogs  and  cats.  He  found  that  under  the  in- 
fluence of  a  few  centigrammes  of  morphine  the  food  remained  in  the 
distended  fundus,  while  the  middle  portion  of  the  stomach,  correspond- 
ing with  the  sphincter  of  the  antrum,  remained  strongly  and  per- 
sistently contracted.  Under  these  conditions  the  peristalsis  of  the 
pyloric  portion  remained  nonnal  and  could  be  readily  seen,  but  the 
pylorus  itself  was  also  tonically  contracted,  and  when  the  contents  of 
the  stomach  finally  passed  into  the  antrum  this  constriction  of  the 
pylorus  retarded  for  hours  its  entrance  into  the  duodenum  (see 
Fig.  13). 

As  a  result,  the  stomach  contents  left  the  stomach  not  after  2-3 
hours,  as  occurs  ordinarily,  but  only  after  8-12-24  hours,  and,  as 
may  be  readily  understood,  in  a  condition  of  more  advanced  digestion 


FIG.  13. — Cat's  stomach  filled  with  bismuth  and  potato  puree,  a,  before  injection  of  morphine; 
6,  22  minutes  after  injection  of  morphine;  c,  1  hour  after  injection  of  morphine,  spasm  of  the 
sphincter  antri  pylori;  d,  3  houra  after  injection  of  morphine. 

and  in  a  more  fluid  form  than  ordinarily.  It  is  clear,  however,  that, 
as  a  result  of  remaining  so  long  in  the  fundus,  fermentation  of  the 
stomach  contents  may  under  these  conditions  occur  to  a  disturbing 
degree,  just  as  in  conditions  of  motor  insufficiency  of  the  stomach 
due  to  pathological  causes,  a  fact  which  should  be  remembered  in 
treating  gastritis,  ulcer,  and  similar  conditions.  This  retardation  of 
the  emptying  of  the  stomach  by  morphine  may  also  affect  the  rapidity 
with  which  drugs  are  absorbed. 

In  man  these  effects  on  the  gastric  motility  result  only  from  rather 
rger  doses  of  morphine,  amounting  to  one  centigramme  or  more. 
Smaller  doses,  such  as  5.0  milligrammes  administered  subcutaneously 
or  ~by  mouth,  usually  increase  the  peristaltic  movements  of  the 
stomach  without  causing  spasm  of  the  pylorus,  and  are  apt  to  accele- 
rate the  rate  at  which  the  stomach  is  emptied  (v.  d.  Velden) . 

The  same  accelerating  influence  of  small  doses  has  been  observed  in  dogs, 
in  which  at  the  same  time  the  secretion  of  the  gastric  juice  is  distinctly  inhibited, 
that  the  stomach  contents  reach  the  duodenum   in  a  less  digested  and  drier 
dition  than  normally,  but  some  hours  later  free  secretion  of  the  gastric  juice 
rs  spontaneously    ( Cohnheim ) . 


190  PHARMACOLOGY  OF  THE  DIGESTION 

BIBLIOGRAPHY 

Cohnheim:  u.  Modrakowski:    Z.  f.  phyaiol.  Chem.,  1911,  vol.  71,  p.  273. 

Hirsch:     Zentralbl.  f.  inn.  Med.,   1901,  vol.  33. 

Magnus:   Pfluger's  Arch.,  1908,  vol.  122,  here  literature. 

Schick:   Wien.  klin.  Wochv   1910,  No.  34. 

v.  d.  Velden:    Verh.  Kongr.  inn.  Med.,  Wiesbaden,  1910,  p.  339. 

THE  MOVEMENTS  OF  THE  INTESTINE 

The  movements  of  the  intestine  consist: 

First,  of  interrupted  progressive  rhythmic  contractions  of  the 
circular  and  longitudinal  fibres,  the  so-called  pendulum  movements, 
which  have  for  their  object  the  division,  mixing,  and  moving  about  of 
the  contents  of  the  intestine ; 

Second,  of  the  true  peristalsis,  which  is  excited  reflexly  by  the 
distention  and  chemical  stimulation  caused  by  the  intestinal  contents, 
and  in  which  tonic  contraction  above  the  stimulated  portion  and 
relaxation  below  it  gradually  moves  the  intestinal  contents  downward 
and  finally  aids  in  expelling  the  faeces  (Bayliss  and  Starling)  ; 

Third,  violent  sudden  waves  of  contraction  passing  downward 
over  large  segments  of  the  small  intestine,  the  so-called  rolling  move- 
ments (Braam  Houkgeest,  Cannon,  Meltzer  and  Auer) ,  which  force 
the  intestinal  contents  forward  through  long  stretches  of  the  small 
intestine,  and  which,  according  to  Meltzer  and  Auer,  are  exited  by  a 
simultaneous  augmentation  of  the  vagus  tone  and  weakening  of  the 
sympathetic  inhibitory  impulses. 

All  these  intestinal  movements,  like  those  of  the  stomach,  are  con- 
trolled by  the  automatic  action  of  Auerbach's  plexus,  and  also  by 
stimulating  impulses  through  the  vagus  and  the  hypogastric  and 
inhibiting  impulses  from  the  sympathetic  through  the  splanchnic. 

PHARMACOLOGICAL  ACTIONS  ON  THE  PERIPHERAL  AUTONOMIC 

ORGANS 

Consequently,  all  the  intestinal  movements,  like  those  of  the 
stomach,  may  be  influenced  by  autonomic  drugs,  and  may  be  EXCITED, 
and,  under  certain  conditions,  to  such  an  extent  that  tonic  contraction 
results,  by  the  action  of  PILOCARPINE,  PHYSOSTIGMINE,  etc.,  on  the  vagus 
nerve-endings,  while  they  may  be  SUPPRESSED  by  ATROPINE  in  so  far  as 
they  are  due  to  excitation  produced  by  vagal  impulses.  In  veterinary 
medicine  pilocarpine  and  physostigmine  are  used  in  colic  occurring 
in  horses  and  cattle,  while  physostigmine,  in  the  form  of  subcutaneous 
injections  of  %-1.0  mg.  of  its  salicylate,  has  recently  been  employed 
in  human  patients  for  the  purpose  of  securing  rapid  and  complete 
emptying  of  the  bowels.  These  autonomic  drugs  act  essentially  only 
on  the  vagus  endings, — that  is  to  say,  they  act  independently  of  the 
automatic  Auerbach  's  plexuses  and  of  the  sympathetic  nervous  system. 

Auerbach's  system,  correctly  named  by  Langley  the  "  enteric  sys- 
tem," acts  entirely  independently  and  maintains  the  automatic  and 


MOTOR  FUNCTION  OF  INTESTINE 


191 


reflex  play  of  the  intestinal  movements  (Magnus}.  Its  stimulation, 
however,  never  causes  a  tonic  contraction  of  the  bowel,  such  as  occurs 
from  strong  stimulation  of  the  vagus  endings,  but  only  a  strengthen- 
ing and  acceleration  of  the  contractions.  Its  ganglia  are  stimulated 
by  small  doses  of  atropine  and  nicotine  and  also  by  strychnine  (Lang- 
ley  and  Magnus),  and  are  paralyzed  by  larger  amounts  of  atropine 
and  nicotine,  which,  however,  are  so  large  that  in  man  these  effects 
are  never  observed,  not  even  in  poisoning  by  these  drugs. 

PHARMACOLOGICAL  ACTIONS  ON  THE  PERIPHERAL  SYMPATHETIC 

ORGANS 

All  the  motor  impulses  from  Auerbach's  plexus  and  from  the  vagus 
taken  together  can,  however,  be  inhibited  by  strong  stimulation  of  the 


Auerbach's  plexus,  which  is — 
stimulated  by  small  amounts  of  atrop 
paralyzed  by  larger  amounts  of  at 


B  Vagus  plexus  on  the  terosa 


Inhibiting  nerve-endings  which 
are  excited  by  epinephrin. 

Fio.  14. 


Vagus  nerve-endings  which  are  excited 
by  pilocarpine,  choline,  etc.,  and  para- 
lyzed by  small  amounts  of  atropine. 


sympathetic  nerve  or  of  its  terminal  organs.  This  may  be  produced 
by  small  doses  of  NICOTINE,  which  stimulate  the  sympathetic  ganglia 
and  also  temporarily  the  sympathetic  nerve-endings,  and  can  be  even 
more  effectively  produced  by  EPINEPHRIN,  which,  when  injected  intra- 
venously, acts  on  the  sympathetic  inhibitory  mechanism  in  the  walls 
of  the  intestine  and  causes  their  muscles  to  relax  and  remain  quiet. 

Those  movements  of  the  intestine  which  are  excited  by  anything  acting 
directly  upon  the  intestinal  musculature  independently  of  any  action  on  its  ner- 
vous mechanism,  are  not  at  all  inhibited  Ly  atropine  and  but  slightly  or  not  at 
all  by  epinephrin.  Such  probably  myogenic  excitation  may  be  caused  by  salts 
of  barium,  and  somewhat  less  energetically  by  poisons  of  the  digitalis  group 
(Magnus).  However,  such  pharmacological  actions  are  of  no  practical  signifi- 
cance. 

These  facts  and  relationships  may  be  diagramatically  indicated 
as  in  Fig.  14. 


192  PHARMACOLOGY  OF  THE  DIGESTION 

ATROPINE'S  pharmacological  actions  in  the  intestine  are  particu- 
larly remarkable.  These  are  in  part  of  an  opposing  or  contradictory 
nature,  for  through  Auerbach's  plexus  this  drug  excites  motor  activ- 
ity while  by  benumbing  the  excitomotor  nerve-endings  of  the  vagus 
it  relaxes  and  quiets  them.  If  to  begin  with  the  vagal  tone  is  not  con- 
siderable, administration  of  atropine  will  produce  little  effect  upon  it, 
but  in  such  case  it  will  markedly  augment  the  rhythmic  and  reflex 
nervous  stimuli  originating  in  Auerbach  's  plexus,  and  as  a  result  peri- 
stalsis will  be  actively  augmented. 

The  opposite  effect  will  be  produced  if  at  the  time  of  its  adminis- 
tration the  vagal  tone  is  exerting  a  strongly  preponderating  influence, 
as  is  the  case  in  cerebral  vagus  stimulation  or  in  spasm  produced 
by  the  action  of  pilocarpine,  neurin,  etc.,  in  lead  poisoning,  or  in 
inflammatory  irritation.  In  such  conditions  atropine,  even  in  small 
doses,  will  eliminate  the  chief  factor  causing  the  abnormal  tonic  con- 
tractions, and  in  this  fashion  it  will  cause  relaxation  and  quieting  of 
the  intestine. 

The  above  explains  the  employment  of  belladonna  preparations — 0.02-0.05 
gm.  of  the  extract  by  mouth  or  %  -2.0  mg.  of  atropine  sulphate  subcutaneously — • 
on  the  one  hand  in  a  tonic  constipation,  either  alone  or  combined  with  cathartics, 
and  on  the  other  hand  in  spastic  constipation,  in  which  a  persistent  abnormally 
increased  tone  of  certain  portions  of  the  intestines,  particularly  of  the  internal 
sphincter  (Frankl-Hochwart  u.  Frohlich) ,  exists,  or  in  the  acute  inhibition  of 
all  intestinal  movement  caused  by  a  localized  spasm  of  the  intestinal  muscle 
such  as  occurs  in  ileus  or  intussusception. 

MORPHINE,  the  constipating  action  of  which  has  long  been  known, 
also  acts  on  the  intestine  at  various  points.  The  constipation  induced 
by  it  is  due  to  several  factors,  one  important  one  being  the  persistent 
closure  of  the  pylorus  which  has  been  already  mentioned,  and  which 
greatly  retards  the  passage  of  the  chyme  into  the  intestine,  thus  les- 
sening the  natural  stimulus  for  peristalsis  (Magnus),  while  the  tem- 
porary inhibition  of  gastric  and  pancreatic  secretion  produces  a 
similar  effect  (Cohnheim  u.  Modrakowski) .  In  addition,  morphine 
diminishes  the  excitability  of  the  vagus  endings  and  also  of  the  sen- 
sory nerve-endings  in  the  walls  of  the  intestines  (Jacob j,  Pohl,  Spitzer) 
and  augments  the  spinal  tone  of  the  inhibitory  splanchnic  nerve  (Pal 
u.  Berggrun,  Spitzer}. 

The  above  experimentally  proved  statements  are,  it  is  true,  not 
generally  accepted,  but  have  in  no  way  been  contradicted.  Recently 
they  have  received  a  certain  confirmation  by  the  observation  that  the 
violently  increased  peristalsis  in  the  large  and  small  intestines  caused 
by  decoctions  of  colocynth  is  visibly  quieted  by  morphine,  and  even 
more  efficiently  by  opium,  while  the  accompanying  inflammatory 
transudation  of  fluid  into  the  intestine  is  markedly  diminished  (Padt- 
berg).  On  the  other  hand,  in  cats,  in  which  inflammatory  irritation 
of  the  small  intestine  was  causing  abnormally  active  peristalsis,  this 
quieting  effect  of  morphine  could  not  be  observed  (Magnus). 


MOTOR  FUNCTION  OF  INTESTINE  193 

It  is  not  known  whether  or  not  the  ileocolie  sphincter  is,  like  that 
of  the  pylorus,  tonically  contracted  by  morphine,  but  it  is  probable 
that  this  is  the  case. 

From  the  above  it  may  be  seen  that  under  certain  conditions  mor- 
phine may  cause  the  intestine  to  become  entirely  or  almost  entirely 
quiet.  Such  a  quieting  of  movements  being  of  essential  value  in 
treating  inflammatory  processes,  not  only  in  the  intestine  but  in  all 
organs,  it  follows  that  opium  is  one  of  the  curative  agents  which  could 
least  be  spared  in  acute  peritonitis  and  enteritis.  The  fact  that  it 
has  not  been  possible  to  observe  with  the  X-ray  methods  this  quieting 
of  the  intestine  by  morphine  in  no  way  speaks  against  its  exerting  this 
action,  for  the  effect  of  the  drug  depends  on  the  momentary  tone  and 
functional  capacity  of  the  inhibitory  splanchnic  centres  and  nerve- 
endings,  and  we  do  not  as  yet  know  how  these  or  the  automatic 
Auerbach's  centres  behave  in  an  intestine  which  is  inflamed  and 
hyperasmic.*  As,  furthermore,  morphine  also  inhibits  the  secretion 
of  the  succus  entericus,  this  action  will  also  aid  in  causing  constipation 
and  in  quieting  peristalsis.  It  goes  without  saying  that,  in  addition, 
the  general  action  of  morphine  in  relieving  pain  may  also  be  of  value 
in  these  conditions  by  calming  the  patients  and  softening  the  reflexly 
contracted  abdominal  muscles,  etc. 

Opium  is  more  efficient  than  pure  morphine  when,  the  indication 
is  simply  to  quiet  the  stomach  and  intestine,  for  the  other  alkaloids' 
contained  in  opium  also  have  a  constipating  but  almost  no  narcotizing 
action,  f  so  that  the  desired  end  may  be  attained  by  a  smaller  $  and 
less  narcotic  dose  of  opium  than  of  pure  morphine  (Gottlieb  u.  v.  d. 
Eeckhout). 

BIBLIOGRAPHY 

Bayliss  and  Starling:  Journ.  of  Physiol.,  1899,  vol.  24,  and  1902,  vol.  26. 

Cannon:  Am.  Journ.  of  Physiol.,  1902,  vol.  6. 

Cohnheim  u.  Modrakowski:    Ztschr.  f.  physiol.  Chem.,  1911,  vol.  71,  p.  273. 

v.  Frankl-Hochwart  u.  Frohlich:   Pfliiger's  Arch.,  1900,  vol.  81,  p.  420. 

Gottlieb  u.  v.  d.  Eeckhout:    Arch.  f.  exp.  Path.  u.  Pharm.,  Suppl.,  1908. 

Houkgeest,  Braam:  Pfliiger's  Arch.,  1872,  vol.  26. 

Jacobj:  Arch.  f.  exp.  Path.  u.  Ther.,  1891,  vol.  29. 

Langley  and  Magnus:   Journ.  of  Phys.,  1905,  vol.  33,  and  1907,  vol.  36. 

Magnus:    Pfliiger's  Arch.,  1904,  vol.  102;  1905,  vol.  108;  1908,  vol.  122,  p.  261. 

Meltzer  u.  Auer:  Am.  Journ.  of  Physiol.,  1907,  vol.  20,  here  lit. 

Padtberg:   Pfliiger's  Arch.,  1911,  vol.  139,  p.  318. 

Pal  u.  Berggriin:   Strieker's  Arb.,   1890. 

Pohl:   Arch.  f.  exp.  Path.  u.  Ther.,  1894,  vol.  34. 

Schick:  Wien.  klin.  Woch.,  1910,  No.  34. 

Spitzer:  Virchow's  Arch.,  1891,  vol.  123. 

CATHARTICS 

Cathartics  are  medicines  which  accelerate  or  bring  about  the 
passage  of  the  intestinal  contents  along  the  alimentary  tract  and  cause 

*  See  the  action  in  irritation  caused  by  colocynth,  p.  192. 

t  At  any  rate  in  cats. 

J  Smaller,  that  is,  in  respect  to  the  amount  of  morphine  contained. 

13 


194  PHARMACOLOGY  OF  THE  DIGESTION 

emptying  of  the  bowel.  The  act  of  defecation  is  accomplished  by  the 
simultaneous  peristaltic  contraction  of  the  rectum  and  the  opening  of 
the  internal  sphincter  of  the  anus,  while  at  the  same  time  colonic 
peristalsis  is  reflexly  excited.  It  is  not  exactly  known  just  what 
normal  impulses  in  the  rectum  inaugurate  the  initial  reflex  for  defeca- 
tion, but  probably  a  certain  degree  of  fulness  and  of  consistency  of 
its  contents  form  the  adequate  stimulus,  although  the  desire  for  stool 
may  be  present  even  when  the  rectum  is  empty,  as  in  tenesmus,  and, 
on  the  other  hand,  may  for  a  long  time  be  lacking  in  spite  of  marked 
and  at  times  in  spite  of  immoderate  distention  by  solid  fecal  matter. 
Probably  this  is  due  to  the  fact  that  the  excitability  of  the  rectal  reflex 
mechanism  varies  greatly  under  various  conditions. 

ENEMATA,  ETC. — As  a  rule,  defecation  may  be  artificially  excited 
by  strong  local  irritation  of  the  rectum,  produced  either  by  mechanical 
distention  with  a  sufficiently  large  amount  of  fluid  rapidly  injected, 
or  induced  chemically  by  the  employment  of  proper  substances. 
Enemata  of  water  act  in  the  former  fashion,  the  coldness  of  the 
fluid  augmenting  the  effect;  while  various  irritating  substances  act 
in  the  latter  fashion,  for  example,  solutions  of  soap  or  soap  cones, 
enemata  of  concentrated  solutions  of  salt,  or,  in  an  especially  con- 
venient manner,  a  few  cubic  centimetres  of  glycerin,  which,  like  the 
salts,  stimulates  the  nerves  in  the  mucous  membrane  as  a  result  of 
its  power  of  attracting  water  to  itself.  If  the  fecal  masses  in  the 
colon  and  rectum  are  very  hard,  dry,  and  large,  the  peristaltic  move- 
ments of  the  intestine  may  prove  ineffectual,  and  in  such  cases  it  may 
be  necessary  first  to  render  these  fecal  concretions  soft  and  slippery. 
This  is  best  accomplished  by  the  gradual  introduction,  at  body  tem- 
perature and  under  the  lowest  possible  pressure,  through  a  rubber 
tube  inserted  as  far  as  possible  into  the  colon,*  of  0.9  per  cent,  sodium 
chloride  solution  containing  a  little  soda,  or  by  injecting  olive  oil 
or  salve-like  paraffin  mixtures  which -are  fluid  at  the  body  temperature 
(Lipowski  u.  Rhode).  Under  these  conditions  the  fluid  may  be 
retained  for  hours  and  soften  the  fecal  concretions. 

Intestinal  Colic. — As  a  rule,  stimulation  of  the  intestinal  mucous  membrane 
does  not  cause  painful  sensation,  and  consequently  chemical  or  mechanical  stimuli 
acting  upon  it  never  directly  cause  pain.  Painful  stimuli  can,  however,  originate 
in  the  peritoneum  when  it  is  markedly  stretched  or  chemically  irritated  by 
inflammatory  products.  Consequently,  violent  peristalsis  of  the  colon  and  rectum, 
when  they  are  filled  with  solid  material,  may  stretch  their  peritoneal  covering 
and  in  this  fashion  cause  pain  or  colic.  In  the  small  intestine,  whose  contents 
are  always  fluid  or  partially  fluid,  even  active  muscular  contractions  do  not 
readily  cause  enough  distention  to  produce  pain,  but  only  enough  to  cause  a 
feeling  of  and  the  noise  resulting  from  the  interrupted  and  irregular  moving 
about  of  the  intestinal  gases. 

*  (It  has  been  definitely  shown  that  it  is  impossible,  under  ordinary  con- 
ditions, to  pass  either  soft  or  stiff  tubes  into  the  colon. — TB.] 


CATHARTICS  195 

MANNER  IN  WHICH  CATHARTICS  ACT 

Cathartic  drugs  produce  their  effects  either  by  directly  exciting 
and  accelerating  the  intestinal  peristalsis  or  by  indirectly  doing  so, 
either  by  lessening  the  normal  absorption  or  by  increasing  the  secre- 
tion of  the  intestinal  glands  and  in  this  way  keeping  the  contents  of 
the  intestine  fluid  and  voluminous. 

From  the  character  of  the  stools  it  is  not  possible  to  distinguish 
sharply  between  these  factors,  for  on  the  one  hand  abnormally  active 
peristalsis  does  not  allow  the  intestine  to  concentrate  its  contents  by 
absorption  of  the  fluid,  and  on  the  other  the  accumulation  of  abnor- 
mally large  amounts  of  fluid  in  the  intestine  reflexly  excites  active 
peristalsis. 

The  quantities  of  fluid  which  under  the  influence  of  the  ingested 
food  are  poured  out  into  the  intestine  in  the  course  of  the  day  and 
which  are  generally  almost  completely  reabsorbed  may  amount  to  as 
much  as  several  litres. 

Bidder  and  Schmidt  have  estimated  them  as  amounting  in  the  adult  man 
to  9  litres,  composed  of  saliva  1.5  L.,  bile  1.5  L.,  gastric  juice  6  L.,  pancreatic 
juice  0.2  L.,  and  succus  intericus  0.2  L. ;  but  here  in  all  probability  the  gastric 
juice  is  estimated  at  too  high  a  figure.  According  to  newer  observations  in  man, 
there  are  excreted  in  24  hours:  of  saliva  700-1000  c.c.  or  more  (Tuczek, 
Sommerfeld,  Umber),  of  bile  600-900  c.c.  (Ranke,  Wittich,  Hoppe-Heyler) ,  pan- 
creatic juice  600-800  c.c.  (Pfaff),  gastric  juice  1000-2000  c.c.  ((rla-ssner) ,  in  all 
3-4%  litres. 

From  these  figures  it  is  evident  that  even  comparatively  slight 
interference  with  the  reabsorption  may  result  in  a  sufficient  quantity 
of  fluid  material  reaching  the  rectum  to  cause  a  soft  or  diarrhoea! 
stool.  "When  the  absorption  is  entirely  inhibited,  as  in  cholera,  con- 
tinual diarrhoeal  movements  occur,  interrupted  by  short  periods  of 
rest,  and,  as  a  result,  the  body  loses  an  enormous  amount  of  fluid  and 
the  blood  becomes  markedly  concentrated  (Schmidt).  Under  these 
conditions  the  fluid  material  evacuated  corresponds  exactly  in  its 
chemical  constitution  to  normal  succus  entericus  (p.  171) . 

ESSENTIAL  PROPERTIES  OF  CATHARTICS. — In  order  for  a  substance 
to  be  suitable  for  use  as  a  cathartic,  it  should  not  act  appreciably 
upon  the  gastric  mucous  membrane,  but  should  become  active  only 
when  it  reaches  the  intestine,  where,  under  the  influence  of  its  new 
environment,  it  is  transformed  into  a  substance  which  can  excite  peri- 
stalsis or  secretory  activity.  According  as  this  transformation  occurs 
in  the  small  intestine  or  only  after  the  drug  reaches  the  large  gut,  it 
will  develop  its  cathartic  action  in  the  small  intestine  or  in  the  large 
intestine.  In  the  small  intestine  the  alkaline  succus  entericus,  bile,  and 
pancreatic  secretion,  with  its  fat-splitting  ferment,  are  responsible 
for  such  transformations,  while  in  the  colon  they  result  from  chemical 
reactions,  more  particularly  from  reductions  due  to  the  activity  of 
putrefactive  bacteria. 


196  PHARMACOLOGY  OF  THE  DIGESTION 

Under  normal  conditions  putrefaction  does  not  occur  in  the  small  gut,  but 
only  below  the  ileocsecal  valve,  as  is  evidenced  by  the  presence  of  H2S  in  the  large 
and  its  absence  in  the  small  intestine. 

As  all  cathartic  actions  are  due  to  reactions  taking  place  on  the 
surface  of  the  intestinal  mucous  membrane,  the  efficiency  of  cathartic 
drugs  will  be,  at  least  in  part,  dependent  on  the  extent  to  which 
they  are  able  to  act  throughout  the  intestine.  F'rom  this  it  may  be 
concluded  that  cathartics  must  be  absorbed  only  with  difficulty  or  not 
at  all,  and  that  those  acting  in  the  small  intestine  must  pass  along 
through  at  least  the  largest  portion  of  it  while  the  others  must  be 
able  to  reach  the  colon. 

From  these  points  of  view  the  cathartics  may  in  general  terms  be 
arranged  in  the  following  groups : 

1.  GROUPS    INTERFERING    WITH    THE    ABSORPTION    THROUGHOUT    THE 

WHOLE  INTESTINE. — In  this  group  are  included  those  substances  which 
act  osmotically,  such  as  the  poorly  absorbable  salts  and  sugars  and 
also  calomel.  According  to  circumstances  and  the  concentrations 
administered,  they  produce  their  effect  in  from  one  to  twenty  hours 
and  with  more  or  less  rumbling  of  the  bowels  but  without  much  colic. 

2.  DRUGS  WHOSE  CHIEF  ACTION  is  ON  THE  MOTOR  FUNCTIONS  OF  THE 
SMALL  INTESTINE. — These  include  certain  oils,  colocynthin,  and  a  num- 
ber of  resinous  acids,  and  act  in  from  2  to  4  hours  with  more  or  less 
rumbling  of  the  bowel  but  without  colic. 

3.  DRUGS  WHICH  OWE  THEIR  EFFECTS  ESSENTIALLY  TO  THEIR  ACTION 

ON    THE    MOVEMENTS    OF    THE    LARGE    INTESTINE. In    this    gTOUp    are 

sulphur,  the  anthracene  derivatives,  and  phenolphthalein.  They  act 
in  about  10-15  hours  without  causing  rumbling  of  the  bowels  but  often 
causing  colicky  pains. 

BIBLIOGRAPHY 

Glassner:  Ztschr.  f.  physiol.  Chem.,  1904,  vol.  40. 

Lipowski  u.  Rhode:   Med.  Klinik,  1909,  No.  48. 

Pawlow:  Die  Arbeit  d.  Verdauungsdriisen,  Wiesbaden,   1898,  p.  106. 

Pfaff:   1877,  Journ.  of  the  Boston  Soc.  of  Med.,  vol.  2,  No.  -2. 

Ranke:   1871,  cited  from  Hoppe-Seyler's  Handb.,  p.  286. 

Schmidt,  C. :  Die  epid.  Cholera,  Leipzig  u.  Mittau,  1850,  p.  72. 

Sommerfeld:   Dubois'  Arch.,  Suppl.,   1905. 

Tuczek:   Ztschr.  f.  Biol.,  1876,  vol.  12. 

Umber :   Berl.  klin.  Woch.,  1905,  No.  42. 

Wittich:    1872,  cited  from  Hoppe-Seyler's  Handb.,  p.  286. 

1.  CATHARTICS  INTERFERING  WITH  ABSORPTION 
GROUP  OF   SALINE   CATHARTICS 

As  has  already  been  mentioned,  solutions  of  crystalloids  diffusing 
poorly  are  in  general  poorly  absorbed  (Hober,  Koranyi,  RicMer),  and, 
inasmuch  as,  owing  to  their  power  of  attracting  water,  they  are  able 
to  retain  their  water  of  solution  and  even  at  times  to  increase  it, 
they  prevent  or  retard  the  absorption  of  the  fluid  with  which  they  are 
administered  or  that  resulting  from  secretion  in  the  small  intestine. 


SALINE  CATHARTICS 


197 


Consequently,  they  cause  the  accumulation  in  the  intestine  of  abnor- 
mally large  amounts  of  fluid,  which  pass  into  the  colon  and  rectum 
and  produce  watery  fecal  discharges.  This  action  is  aided  and  aug- 
mented by  the  increased  intestinal  secretion  which  results  from  the 
reflex  stimulation  of  the  intestinal  glands  by  the  concentrated  salt 
solution.  In  this  fashion  the  sulphates,  Na2S04,  or  Glauber's  salts, 
and  MgS04,  or  Epsom  salts,  act  as  particularly  effective  cathartics. 

This  conception  of  the  fashion  in  which  the  saline  cathartics  act,  which  is 
based  upon  the  investigations  of  Buchheim  and  his  collaborators,  and  particu- 
larly on  those  of  Matthew  Hay,  finds  its  proofs  in  many  facts,  but  particularly 
in  the  fact  that  the  fluid  bowel  movements  resulting  from  the  administration 
of  saline  cathartics  possess  the  characteristic  properties  of  normal  intestinal 
secretion  in  both  their  fermentative  properties  and  their  chemical  composition, 
which  differs  quite  as  much  from  that  of  an  inflammatory  transudate  or  exudate 
as  from  that  of  a  fluid  diluted  simply  as  a  result  of  osmotic  diffusion  from  the 
tissues.  In  every  particular  they  correspond  very  closely  to  normal  succus 
entericus  obtained  from  intestinal  fistulas,  as  is  shown  by  the  following  table: 


Human  serum 

Acute  inflamma- 
tory transudate 

Chronic  perito- 
neal exudate 

Pleural  exudate 

Normal  succus 
entericus 

Diarrhoea!  stool 
Hay'' 

Cholera  stool 
(C.  Schmidt) 

Moreau 

Smith 

I 

II 

Solids  

9.2 
7.6 
1.6 

8.1 

7.2 
0.9 

3.0 

2.2 
0.8 

3.4 
2.6 
0.8 

1.3 
0.4 
0.9 

1.1 

0.5 
0.6 

1.6 
0.8 
0.8 

1.2 
0.3 
0.9 

1.5 
0.7 
0.8 

Organic  

Inorganic  

Ury  has  recently  investigated  in  human  subjects  the  action  of  Apenta  water, 
which  contains  about  15.5  gm.  Na2SO4  and  2.0  gm.  NaCl  per  litre,  and  of  solutions 
of  magnesium  sulphate,  in  which  he  determined  the  composition  of  the  evacuated 
faeces.  His  findings  have  led  him  to  conclude  that  large  amounts  of  water  are 
excreted  in  the  intestine  by  a  sort  of  capillary  transudation,  for  he  found  these 
stools  to  contain  very  small  amounts  of  ferments,  and  he  therefore  concluded  that 
the  secretions  of  the  intestinal  glands  made  up  but  a  very  small  portion  of  the 
fluid  evacuated.  However,  it  has  not  yet  been  determined  whether  or  not  these 
ferments  are  not  in  large  part  weakened  or  destroyed  during  their  passage  through 
the  large  intestine  (Grower),  and,  moreover,  the  sodium  and  chlorine  contents  of 
the  fluids  evacuated,  even  in  Ury's  experiments,  correspond  quite  closely  to  that 
of  the  normal  intestinal  secretion. 

Various  other  authors,  and  comparatively  recently  MacCallum,  have 
assumed  that  the  salines  after  absorption  into  the  blood  stimulate  the  motor 
and  secretory  mechanisms  of  the  intestinal  wall  and  in  this  fashion  cause 
diarrhoea.  However,  in  contradiction  to  this  view,  it  has  recently  once  more 
been  definitely  shown  that  intravenous  or  subcutaneous  injections  of  saline  cathar- 
tics do  not  cause  diarrhoea,  but  that  when  concentrated  solutions  are  used  they 
actually  cause  persistent  constipation,  for  by  causing  an  increased  diuresis 
they  dehydrate  the  blood  and  tissues  quite  markedly  (Frankl,  Auer).  However, 
if  very  large  amounts  of  dilute  salt  solutions  be  administered  subcutaneously, 
so  large  a  portion  of  this  may  be  excreted  into  the  intestine  that  it  excites 
diarrhoea,  just  as  it  does  when  administered  internally.  Further,  if  a  concen- 
trated salt  solution  be  injected  under  the  skin  of  the  abdomen,  it,  like  other 
irritating  substances,  may  cause  a  more  or  less  violent  local  irritation,  which 
may  reflexly  cause  hyperaemia  and  stimulation  of  the  intestines  innervated  from 
the  same  segment  of  the  spinal  cord,  and  in  this  fashion  cause  a  diarrhoea 


198  PHARMACOLOGY  OF  THE  DIGESTION 

(Hay).  From  other  portions  of  the  skin,  however,  this  reflex  cannot :  be 
obtained. 

MacCallum's  assumption  was  based  on  the  observation  that  intravenous 
injections  of  very  small  amounts  of  Glauber's  or  Epsom  salts,  or  the  painting 
of  an  exposed  loop  of  the  intestine  with  such  solutions,  excited  a  muscular  con- 
traction of  the  gut  and  a  secretion  by  the  mucous  membrane.  While  it  is 
true  that  this  effect  may  be  regularly  obtained  by  the  local  application  of  such 
solutions,  intravenous  injections  are  only  occasionally  followed  by  such  effect, 
and,  even  when  it  does  occur,  the  motor  stimulation  lasts  only  a  few  seconds, 
or  at  the  most  a  few  minutes,  and  exerts  no  appreciable  influence  on  the  trans- 
portation downward  of  the  intestinal  contents  or  their  evacuation  (Frankl). 
Padtberg  has  also  recently  confirmed  the  correctness  of  Buchheim's  views. 

In  another  indirect  connection,  however,  MacCallum's  belief  in  the  specific 
chemical  activity  of  the  saline  cathartics  finds  a  support  and  basis.  As  already 
mentioned  (see  foot-note,  p.  175),  Wallace  and  Cushny  have  looked  upon  the 
calcium-precipitating  power  of  the  salines  as  one  of  the  causal  factors  in  their 
cathartic  action,  and  it  is  a  fact  that  the  intestinal  wall  is  deprived  *  of  its 
calcium  by  those  anions  which  precipitate  calcium,  among  which  is  the  anion 
which  is  formed  from  castor  oil.  This  removal  of  calcium  probably  augments 
quite  generally  the  effect  of  motor  and  secretory  stimuli  (/.  Loeb,  Chiari  u. 
Frohlich ) . 

The  concentration  of  the  saline  solutions  exerts  an  important 
influence  on  their  behavior  and  their  effects  in  the  intestine,  for  the 
following  reasons.  High  concentrations  (for  Na2S04  10-25  per  cent.) 
combine  with  and  hold  fast  large  amounts  of  the  gradually  secreted 
gastric  juice,  and  continue  to  do  this  until  the  salt  concentration  has 
sunk  to  about  3  per  cent.  When  this  dilution  has  been  attained, 
the  solution  has  lost  its  power  of  combining  with  the  water  or,  what  in 
this  case  means  almost  the  same  thing,  has  lost  the  power  of  preventing 
absorption,  and  in  fact  a  portion  of  such  a  diluted  solution  is  absorbed 
and  enters  the  blood,  although  by  far  the  larger  portion  leaves  the 
intestine  in  the  watery  stools.  As  the  dilution  of  the  saline  solution — 
that  is  to  say,  the  augmentation  of  the  amount  of  fluid  in  the  intes- 
tine— results  practically  only  from  the  gradual  secretion  of  the 
digestive  juices,  it  may  take  many  hours  before  the  quantity  becomes 
large  enough  to  produce  a  diarrhoeal  evacuation.  For  example,  after 
the  administration  of  the  dry  salt  to  a  dog,  defecation  occurs  only  after 
about  25  hours,  and,  after  the  administration  of  a  20  per  cent,  solution 
to  man,  only  after  16  hours.  Moreover,  catharsis  is  produced  by  salts 
thus  administered  only  if  the  intestine  is  able  to  furnish  a  sufficiently 
large  amount  of  secretions,  and  this  is  dependent  on  the  amount  of 
water  present  in  the  blood  and  in  the  tissues.  If  the  dog  has  received 
no  fluid  and  only  dry  food  for  one  or  two  days,  the  secretions  of  the 
alimentary  tract  are  so  scanty  that  a  concentrated  solution  of  Glauber 's 
salt  may  be  administered  without  producing  any  catharsis. 

If,  on  the  other  hand,  a  diluted  (5  per  cent,  or  less)  solution  be 
administered,  it  does  not  retain  the  fluid  secreted  by  the  digestive 

*  The  calcium  is  in  part  actually  removed  and  in  part  precipitated  in  insolu- 
ble form  in  the  tissues  forming  the  intestinal  wall.  Calomel  also  produces 
a  similar  diminution  of  the  calcium  content  of  the  intestinal  walls. 


SALINE  CATHARTICS 


199 


organs,  and  consequently  does  not  increase  in  amount,  but  in  fact  is 
somewhat  diminished,  because  a  portion  of  the  dilute  solution  under- 
goes absorption.  If  the  amount  administered  was  by  itself  large 
enough,  the  unabsorbed  portion  passes  rapidly  into  the  colon  and 
causes  a  diarrhoea!  stool,  which  may  consequently  occur  very  soon, 
in  1-2  hours,  and  which  is  quite  uninfluenced  by  the  water  content 
of  the  blood  and  tissues. 


Red  cells  in  millions 

per  cu.  mm. 

Ma 

»|  =21  .OWaiSOt 

g 

in  5% 

solution 

i             •••^         l 

-^-—  ' 

^"—  -*  —  -  - 

-'- 

••" 

', 

1 

Bed 
per 

7 

<? 
S 
& 

cells  in  millions 
cu.  mm. 

r 

-XM, 

\n  \  =21  .0 
in  26% 

NazSOf 
tolution 

1 

V^ 

\ 

/ 

/J* 


Red  cells  in  millions 
per  cu.  mm. 


It  is  thus  seen  that  the  effect  of  concentrated  and  dilute  solutions 
is  quite  different.  After  administration  of  a  laxative  dose,  for  example 
20  gm.  Na2S04,  in  concentrated  solution,  a  diarrhoeal  evacuation  fol- 
lows in  10^-20  hours  and  water  is  removed  from  the  body,  but  after 
administration  of  a  small  dose  in  dilute  solution, — e.g.,  5  per  cent., 
that  is  to  say  in  a  large  amount  of  water, — diarrhoea  follows  in  1-2 
hours,  and  the  water  content  of  the  body  is  not  affected.  These  effects 
may  be  readily  demonstrated  by  determining  the  red-cell  content  of 
the  blood  before  and  after  the  administration  of  the  salts  (see  Fig.  15). 


200  PHARMACOLOGY  OF  THE  DIGESTION 

In  both  cases  there  may  be  noted  a  temporary  slight  increase  in  the  con- 
centration of  the  blood,  which  occurs  very  late.  This  is  explained  by  the  fact 
that  a  certain  amount  of  the  salt  is  absorbed  and  circulates  around  in  the  blood 
or  is  stored  up  in  the  tissues,  which  later,  when  excreted  through  the  kidneys, 
carries  with  its  solvent  water  which  is  thus  lost  by  the  blood. 

From  these  facts  one  may  draw  the  conclusion,  that,  in  those  cases 
in  which  saline  cathartics  are  to  be  given  for  a  considerable  period  in 
order  to  exert  curative  action  on  the  intestinal  mucous  membrane, 
they  should  be  administered  in  dilute  solutions,  such  as  the  natural 
cathartic  mineral  waters,  and  that,  when  they  are  employed  to  produce 
dehydration,  as  in  dropsy,  they  should  be  given  only  in  concentrated 
solution.  Magnesium  sulphate  (Hay),  which  is  soluble  in  an  equal 
weight  of  water,  and  calcined  magnesia  in  substance  are  the  best  drugs 
to  meet  this  indication. 

Hay's  investigations  also  brought  to  light  another  important  fact, — namely, 
that,  along  with  its  purgative  action,  magnesium  sulphate  causes  the  body  to 
lose  a  certain  amount  of  its  alkali.  This  is  due  to  the  fact  that,  as  this  salt 
is  in  part  decomposed  by  the  carbonic  acid  in  the  intestine,  considerable  amounts 
of  sulphuric  acid  are  absorbed,  which  are  later  excreted  in  the  urine,  combined 
with  soda  and  ammonia  which  is  derived  from  the  body.  Quantitative  deter- 
mination of  the  sulphuric  acid  and  the  magnesium  excreted  in  the  urine  under 
such  conditions  shows  that  the  sulphuric  acid  excreted  in  the  urine  is  sufficient 
to  neutralize  about  ten  times  the  amount  of  magnesium  excreted.  It  is 
thus  clear  that  with  the  continued  administration  of  this  salt  the  body  will  lose 
more  or  less  alkali.  This  it  is  able  to  support  for  a  time  by  utilizing  ammonia 
for  the  neutralization  of  the  excess  of  sulphuric  acid,  but  it  is  not  impossible 
that  when  Epsom  salts  are  persistently  taken  the  organism  may  suffer  some 
damage  as  a  result  of  such  constant  loss  of  alkali,  and  in  practice  it  is  the 
custom,  when  using  saline  cathartics  for  long  periods  of  time,  almost  always  to 
employ  them  in  mixtures  containing  alkaline  carbonates,  such  as  are  present  in 
the  natural  spring  waters  of  Carlsbad,  Marienbad,  etc. 

Effects  on  Utilization  of  Food. — Inasmuch  as  the  small  intestine 
usually  contains,  in  addition  to  the  digestive  juices,  more  or  less  food, 
an  accelerated  emptying  of  the  bowel  and  an  interference  with  the 
absorption  must  exert  an  unfavorable  effect  upon  the  utilization  of 
the  food  ingested.  According  to  the  analyses  available,  it  is  especially 
the  utilization  of  fats  which  suffers,  this  being  due  not  only  to  the 
cathartic  action  of  the  magnesium  salts  but  also  to  the  fact  that  the 
fatty  acids  and  magnesia  form  insoluble  and  consequently  unabsorb- 
able  soaps.  "While  this  interference  with  the  utilization  of  food  is  not 
very  great,  it  is  an  accessory  factor  in  the  reduction  of  weight  obtained 
by  the  use  of  various  salines. 

Effect  on  Intestinal  Flora. — Finally,  among  the  effects  of  the 
thorough  evacuation  and  flushing  of  the  intestine  by  cathartics,  men- 
tion should  be  made  of  their  power  of  removing  from  it  bacteria  and 
their  decomposition  products,  for  it  is  quite  possible  that  numerous 
symptoms  of  disease  are  due  to  the  absorption  of  toxic  substances  from 
the  intestine,  which  give  rise  to  the  so-called  auto-intoxication.  As  all 
attempts  to  accomplish  disinfection,  not  to  speak  of  sterilization, 


SALINE  CATHARTICS  201 

of  the  intestine  by  the  administration  of  disinfectants  have  proved 
unavailing  (Stern),  the  most  efficient  means  of  removing  pathogenic 
micro-organisms  is  repeated  catharsis.  Calomel  appears  to  be  the 
cathartic  best  adapted  for  this  indication,  as  its  cathartic  action  starts 
in  the  small  intestine  and  extends  throughout  the  whole  length  of  the 
bowel,  and  at  the  same  time  it  possesses  some  bactericidal  powers.* 

Effects  on  the  Liver. — It  is  possible  that  such  cleansing  of  the  intes- 
tine plays  an  important  role  in  the  treatment  of  diseases  of  the  liver 
and  of  chronic  intestinal  catarrhs  by  Carlsbad  or  other  saline  waters. 
It  appears  not  improbable  that  under  such  conditions  the  increased 
blood-flow  through  the  vessels  of  the  intestine  and  of  the  liver,  as  also 
the  local  salt  action  of  the  sodium  sulphate  and  the  soda,  which  are 
absorbed  into  the  blood  and  lymph,  may  also  play  an  important  part 
in  producing  curative  effects.  The  favorable  effect  of  the  saline 
cathartics  in  diabetes  mellitus  is  nmch  more  difficult,  in  fact  practically 
impossible,  to  explain. 

This  increased  blood  flow  through  the  whole  portal  system  resulting  from 
the  action  of  the  cathartics  necessarily  causes  a  correspondingly  diminished 
blood  flow  in  other  organs,  such  as  the  lungs,  heart,  etc.  This  has  been  spoken 
of  as  determination  to  the  intestine,  and  is  often  employed  as  a  curative  or 
symptomatically  favorable  action  in  hypersemia  of  the  brain  or  of  the  thoracic 
organs. 

The  chief  drugs  of  this  group  used  in  practice  are  as  follows: 
the  sulphates  of  the  alkalies,  particularly  GLAUBER'S  SALT  or  SODIUM 
SULPHATE,  Na2SO4  -(-  10H2O,  or  -f-  1H20,  containing  according  to  the 
amount  of  its  water  of  crystallization  44  or  88  per  cent,  sodium 
sulphate,  and  EPSOM  SALT,  or  MAGNESIUM  SULPHATE,  MgSO4  -f-  7H20, 
containing  about  50  per  cent,  magnesium  sulphate.  These  two  salts, 
in  doses  of  15-30  gm.  taken  at  one  time  or  at  short  intervals,  are 
efficient  laxatives. 

All  the  sulphates  if  they  remain  long  in  the  large  intestine  undergo 
a  reduction,  with  production  of  hydrogen  sulphide,  an  effect  which 
occasionally  leads  to  disagreeable  borborygmus  and  flatulence. 

As  Antidotes. — As  sulphuric  acid  forms  insoluble  salts  with  barium  and 
lead,  the  soluble  sulphates  may  serve  as  chemical  antidotes  in  lead  or  barium 
poisoning.  Many  toxic  substances,  particularly  the  phenols,  are  conjugated  in  the 
organism  with  sulphuric  acid  from  non-toxic  compounds,  and  consequently  it 
has  been  believed  that  in  carbolic  acid  poisoning  it  was  possible  to  facilitate  or 
augment  the  distoxication  of  the  absorbed  carbolic  acid  by  administering  the 
sulphates.  However,  neither  clinical  experience  nor  laboratory  experiments 
furnish  evidence  that  such  is  the  case  (Tauber). 

Sodium  sulphate  is  the  most  important  ingredient  of  the  waters  of 
Marienbad,  Carlsbad,  and  Tarasp,  while  magnesium  sulphate  is  the 
most  important  ingredient  of  numerous  so-called  bitter  waters,  among 

*  [More  recent  careful  investigation  of  the  disinfectant  action  of  calomel  in 
the  intestine  would  indicate  that  it  possesses  none,  or  at  least  none  of  practical 
value.  See  Harris,  Jour,  of  A.  M.  A.,  1912. — TB.] 


202  PHARMACOLOGY  OF  THE  DIGESTION 

which  may  be  mentioned  those  of  Friedrichshall,  Mergentheim,  Apenta, 
Hunyadi  Janos,  etc.  Artificial  Carlsbad  salts  are  a  mixture  of  salts 
corresponding  approximately  to  the  residue  obtained  by  evaporating 
Carlsbad  water  and  contain  about  44  per  cent.  Na2S04  -+-  1H20 ;  6.0 
gm.  of  these  artificial  salts  in  one  litre  of  water  roughly  represent  the 
natural  Carlsbad  water.  Magnesium  sulphate  is  partially  decomposed 
in  the  intestine  by  the  carbonates  of  the  intestinal  secretions,  and 
bicarbonate  of  magnesium  is  formed,  which  possesses  the  same  power 
of  attracting  water  and  of  causing  catharsis  as  does  the  original  salt. 
When  this  occurs,  the  sulphuric  acid  is  in  large  part  eliminated  in  the 
urine,  temporarily  increasing  its  acidity  (Hay)  (see  p.  200). 

CALCINED  MAGNESIA  or  MAGNESIA  USTA,  although  almost  entirely 
insoluble,  is  transformed  in  the  intestine  into  the  bicarbonate  and 
thus  acts  as  a  cathartic.  On  account  of  its  freedom  from  taste  or 
other  harmful  actions,  this  drug  may  be  readily  administered  to  sus- 
ceptible patients  or  to  small  children,  and  may  also  be  used  with  advan- 
tage to  neutralize  acids  in  the  stomach  and  the  intestine,  or  in  poison- 
ing by  metallic  salts,  to  precipitate  the  metallic  oxides  out  of  their 
solutions  or  more  or  less  absorbable  compounds,  and  in  this  fashion 
to  render  them  harmless,  at  least  for  a  time. 

As  Antidote  for  Arsenic. — With  arsenous  acid  magnesia  forms  a  very  in- 
soluble salt,  and  consequently  it  is  commonly  used,  usually  in  combination  with 
iron  hydroxide,  as  an  antidote  in  arsenical  poisoning.  However,  experiments  on 
animals  poisoned  with  lethal  doses  of  arsenic  have  indicated  the  uselessness  of 
this  treatment  (de  Bucher). 

Toxic  Action  of  Magnesium. — If  absorbed  into  the  circulation,  magnesium 
salts  are  very  poisonous,  even  a  few  decigrammes  administered  intravenously 
to  large  animals  being  sufficient  to  paralyze  the  respiratory  centre.  When  fol- 
lowing subcutaneous  injection  the  toxic  action  develops  gradually,  the  respira- 
tory paralysis  is  preceded  by  a  complete  narcosis  of  the  central  nervous  system, 
which  after  0.8-0.9  gm.  MgCl2  per  kilogramme  of  body  weight  lasts  some  hours, 
and  then  gradually  disappears  as  the  salt  is  excreted.  Intravenous  injection  of 
calcium  salts  overcomes  this  narcosis  almost  instantaneously  (Meltzer  u.  Auer). 
Lower  animals  also  are  narcotized  and  paralyzed  without  primary  stimulation 
by  salts  of  magnesia,  a  fact  which  is  well  known  to  zoologists  and  utilized  by 
them  for  the  fixation  of  animal  organisms  in  natural  free  positions  (Lee  and 
P.  Mayer). 

[Boos  has  called  attention  to  the  very  real  danger  of  serious  or 
fatal  poisoning  from  the  absorption  of  magnesium  sulphate  which  has 
been  given  to  induce  catharsis  and  which  has  failed  to  act.  The  trans- 
lator is  convinced  that  he  has  seen  evidence  of  such  toxic  actions, 
particularly  in  cases  of  postoperative  ileus.  As  sodium  sulphate  is 
equally  efficient  and  quite  harmless,  it  should  be  given  the  preference 
in  any  cases  in  which  there  is  possibility  of  intestinal  obstruction  01 
paresis. — TR.] 

Among     OTHER     SALINE     CATHARTICS     are     sodium     phosphate, 
Na2HPO4  +  12H2O,  containing  40  per  cent,  of  the  salt,  used  in  dosage 
of  20-40  gm. ;  the  rather  insoluble  potassium  bitartrate,  KHC4H4Ofi 
used  in  dosage  of  5.0-10.0  gm.,  the  readily  soluble  Seignette  salt, 


CALOMEL  203 

•potassium  and  sodium  tartrate,  KNaC4H406,  -j-  4H20,  dose  15.0- 
30.0  gni.,  and  also  the  citrates  of  the  alkalies.  Tamarind,  containing 
large  amounts  of  organic  acids,  and  mannite  also  produce  their  laxa- 
tive action  in  a  similar  fashion. 


Auer:   Am.  Journ.  of  Physiol.,  1906,  vol.  17. 

Auer:  Journ.  of  Biol.  Chem.,  1908,  vol.  4. 

Boos:  J.  of  A.  M.  A.,  1910. 

de  Bucher:  Arch,  intern,  de  Pharmacodyn.,  1902,  vol.  10,  p.  414. 

Chiari:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  434. 

Chiari  u.  Frohlich:    Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  64,  p.  214. 

Frankl:   Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  57. 

Grober:  Deut.  Arch.  f.  klin.  Med.,  vol.  83,  Nos.  3  and  4. 

Hay:   The  Physiol.  Action  of  Saline  Cathartics,  Edinburgh,  1884,  p.  160. 

Hay:   The  Lancet,  21st  April,  1883. 

Hay:  Journ.  of  Anat.  and  Physiol.,  1884,  vols.  16  and  17,  literature. 

Hober:    Pfluger's  Arch.,  1898,  vol.  70,  p.  624,  and  1899,  vol.  74,  p.  246. 

Koranyi-Richter:   Hdb.  d.  physik.  Chem.  u.  Med.,  1907,  p.  294  ff.,  Phyaikal.  Chemie 

in  der  Physiol.  d.  Resorption. 

Lee  u.  P.  Mayer:  Mikroskop.  Technik.  f.  Zoologen,  1901. 
Loeb,  J.:  Am.  Journ.  of  Phys.,  1901,  vol.  5,  p.  362. 
Loeb,  J.:   Pfluger's  Arch.,  1902,  vol.  91,  p.  248. 
MacCallum:   Am.  Journ.  of  Physiol.,  1903,  vol.  10. 
MacCallum:   Univ.  of  Calif.  Publ.,  1903,  vol.  1;  1906,  vol.  3. 
Meltzer  u.  Auer:  Amer.  Journ.  of  Physiol.,  1908,  vol.  21,  p.  400. 
Padtberg:   Pfluger's  Arch.,  1909,  vol.  129,  p.  476. 
Stern:  Ztschr.  f.  Hygiene,   1892,  vol.   12. 
Tauber:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36,  p.  197. 
Ury:  Arch.  Verd.,  1909,  vol.  15,  No.  2. 

CALOMEL 

Calomel,    the    mild    chloride    of    mercury,    mercurous    chloride 

^.  ),  should  also  be  considered  here. 
VHg—  Cl/ 

It  occurs  in  the  form  of  a  tasteless  white  powder,  consisting  of  microscopic 
crystals  which  are  insoluble  in  water.  By  the  rapid  cooling  of  its  vapor,  it  may 
be  obtained  as  a  very  fine,  almost  entirely  amorphous  powder.  The  name  calomel 
was  given  on  account  of  the  beautiful  black  color  produced  by  treating  calomel 


with  ammonia,  according  to  the  formula  fg       +  2NH3  =  Hg  (  NH2C1  )  2  +  Hg. 

By  contact  with  the  tissue  fluids,  calomel  is  transformed  into 
soluble  mercuric  compounds,  probably  albuminates,  which,  without 
causing  an  acute  local  toxic  action,  are  absorbed,  and  produce  a  mer- 
curial action  which  develops  very  gradually.  In  the  mucous  mem- 
brane of  the  mouth  and  intestine,  this  action  causes  a  stimulation 
of  glandular  secretions  and  inhibition  of  absorption,  so  that  under 
proper  conditions  it  causes  salivation  and  the  accumulation  of  large 
amounts  of  fluid  in  the  intestine,  with  the  evacuation  of  watery 
stools. 

Mercurial  salivation  may  be  suppressed  by  atropine,  as  may  also  the 
diarrhoea  caused  by  it.  The  actions  on  the  salivary  glands  appear  to  be  due  to 
a  specific  pilocarpine-like  stimulation  of  their  secretory  nerves. 


204  PHARMACOLOGY  OF  THE  DIGESTION 

Calomel  stools  often  have  a  grayish-green  color,  which  is  ordinarily  attrib- 
uted to  biliverdin,  which  is  supposed  to  escape  the  usual  reduction  to  biliprasin 
on  account  of  the  disinfecting  influence  of  calomel.  However,  Dot/on  and  Eufort 
found  that  calomel  produced  the  same  green-colored  stools  even  when  the  bile- 
duct  is  divided  and  the  bile  is  permitted  to  escape  through  a  fistula.  Conse- 
quently, this  green  color  is  due  to  the  presence  of  the  sulphide  of  mercury. 

EFFECT  ON  THE  BILIARY  SECRETION. — The  bile  becomes  more  con- 
centrated, and  is  consequently  secreted  more  slowly,  as  a  result  of  the 
dehydration  which  results  from  catharsis  with  calomel  (Doyon  and 
Bufort)*  ( 

Inasmuch  as  the  first  action  of  calomel  is  limited  to  its  specific 
effect  on  secretion  and  absorption,  and  as  it  causes  no  irritation  or 
inflammation,  but,  on  the  contrary,  by  its  disinfecting  action  combats  to 
a  certain  extent  the  harmful  bacteria  flora  [  ?  see  p.  201. — TR.]  ,  calomel 
may  be  used  without  fear  in  moderate  doses  (0.05-0.3  gm.)  in  adults, 
even  in  the  presence  of  diseased  or  delicate  intestines,  and  also  in 
small  children  (0.01  gm.  for  infants)  and  in  pregnant  women.  As  a 
rule,  painless  catharsis  results  from  its  administration. 

In  order  that  calomel  may  act  without  doing  harm,  however,  it 
must  be  rapidly  and  completely  eliminated  by  the  bowel.  In  the 
presence  of  a  constipation  due  to  intestinal  paresis  from  peritonitis 
or  to  obstruction  of  the  bowel,  calomel  is  a  dangerous  drug,  for  under 
these  conditions  it  will,  little  by  little,  go  completely  into  solution  and 
be  absorbed,  and  cause  the  same  symptoms  of  poisoning  as  does  cor- 
rosive sublimate.  Further,  the  administration  of  calomel  to  patients 
taking  iodides  should  be  avoided,  for,  when  these  two  substances  meet 
each  other  in  the  tissues,  the  caustic  mercuric  iodide  is  formed. 

DIURETIC  EFFECTS. — The  augmentation  of  diuresis  occurring  24-36 
hours  after  the  administration  of  calomel  is  probably  dependent  on  the 
fact  that  calomel  causes  the  accumulation  of  large  quantities  of  fluid 
in  the  intestine,  and  the  fact  that,  if  this  fluid  is  not  rapidly  enough 
evacuated  from  the  large  intestine,  a  large  portion  of  it  will  be  reab- 
sorbed  from  the  colon  and  will  cause  hydraemia  and  resulting  diuresis 
(unpublished  experiments).  This  diuresis  occurs  the  more  rapidly 
and  to  a  greater  extent  the  more  rapidly  the  blood  is  able  to  replace 
from  the  tissues  the  water  lost  as  the  result  of  the  secretion  into  the 
small  intestine  (and  this  is  especially  the  case  in  the  presence  of  a  gen- 
eral anasarca) ,  for  then  the  fluid  absorbed  from  the  colon  is  added  to 
the  blood  and  causes  a  marked  hydraemia.  Moreover,  this  general  effect 
is  the  greater,  the  more  slowly  the  colon  is  emptied  by  defecation. 
Clinical  experience  has  taught  us  that  calomel  causes  a  marked  diu- 
resis where  these  various  essential  conditions  are  present, — i.e.,  in  cases 
with  general  anasarca  and  functionally  capable  kidneys,  and  espe- 
cially when  the  calomel  has  been  given  together  with  opium,  which 
either  retards  the  evacuation  of  the  bowels  or  entirely  prevents  it. 

On  the  kidney  itself,  it  appears  that  calomel,  to  the  extent  to  which 

*  Arch,  de  Physiol.  norm,  et  path.,  1897,  vol.  9,  p.  562. 


205 

it  is  absorbed  in  soluble  modifications,  does  not  act  differently  than 
bichloride  of  mercury  and  many  other  metallic  salts,  in  very  small 
amounts  causing  hyperasmia  and  irritation  and  in  large  amounts  pro- 
ducing serious  damage.  In  the  presence  of  nephritis  it  should,  there- 
fore, not  be  given  (see  chapter  on  Diuresis,  p.  356).  [Many  will 
disagree  with  this  sweeping  statement. — Tr.]  All  the  other  slowly 
developing  actions  of  calomel  administered  internally  or  subcutane- 
ously  and  intramuscularly  are  the  same  as  those  of  other  mercurial 
compounds.  For  further  details  the  reader  is  referred  to  the  chapter 
on  etiotropic  drugs. 

II.  CATHARTICS  ACTING  CHIEFLY  ON  THE  SMALL  INTESTINE 

Neutral  fats  are  passed  through  the  stomach  without  undergoing 
appreciable  decomposition,  but  are  saponified  in  the  small  intestine. 
The  soaps  formed  from  the  animal  and  most  of  the  vegetable  fats  act 
as  very  mild  irritants  to  the  intestinal  mucous  membrane,  accelerating 
peristalsis  only  when  administered  in  considerable  amounts.  In  this 
fashion  20-30  gm.  butter  taken  on  a  fasting  stomach  may  produce 
a  mild  laxative  effect.  However,  the  soap  formed  from  castor  oil 
in  the  intestine  acts  as  a  specific  excitant  of  the  peristalsis  of  the  small 
intestine. 

OLEUM  RICINI,  or  castor  oil,  is  obtained  by  crushing  the  castor-oil 
bean,  and  by  repeated  filtration  is  freed  from  various  impurities, — 
among  others,  from  the  poisonous  proteid  ricin.  It  has  a  flat,  repul- 
sive taste,  and  in  many  individuals  causes  nausea,  probably  because 
it  is  decomposed,  although  only  to  a  small  extent,  in  the  stomach. 
Its  irritant  action  in  the  small  intestine  is  not  intense,  and  never 
enough  to  cause  inflammatory  irritation,  chiefly  because  these  ricinus 
soaps  are  absorbed  in  the  small  intestine,  so  that  their  action  is  not 
persistent.  In  spite  of  this,  however,  a  sufficiently  powerful  effect  on 
the  peristalsis  is  usually  produced,  for  it  acts  on  a  very  large  portion 
of  the  intestine,  as  it  passes  along  the  gut  very  gradually  and  is  only 
gradually  saponified  (H.  Meyer}.  Doses  of  15.0-30.0  gm.  are  followed 
after  6-10  hours  by  one  or  two  soft  stools  without  colic.  Castor  oil 
hardly  ever  reaches  the  large  intestine,  and  consequently  produces  no 
effect  upon  it  (Magnus}.  It  may,  therefore,  without  fear  be  pre- 
scribed for  pregnant  women. 

CROTON  OIL,  oleum  crotonis,  obtained  from  the  seeds  of  Croton 
tiglium,  contains  crotonoleic  acid,  partly  in  a  free  state,  and  other 
unknown  substances.  Consequently,  wherever  applied,  this  drug 
causes  violent  irritation  and  inflammation.  In  doses  of  5.0-20.0  mg. 
(maximal  dose,  0.05  gm.  per  dose)  it  acts  as  a  drastic  purgative. 
When  purified  by  alcohol,  croton  oil  is  neutral  in  reaction,  tasteless, 
and  unirritating,  but,  owing  to  its  saponification  in  the  intestine, 
even  this  in  doses  of  0.05  gm.  causes  violent  diarrhoea  (Buchheim  u. 
Kricli}. 


206  PHARMACOLOGY  OF  THE  DIGESTION 

CERTAIN  RESINOUS  ACIDS  appear  to  act  similarly  to  ricinoleic  acid. 
Among  these  are  the  resins  present  in  the  tuberous  root  of  Ipomo3a 
jalapa  (Jalap)  and  in  the  root  of  Convolvulus  scammonia  (Scam- 
mony)  and  many  others.  These  are  all  acid  anhydrides  of  a  glu- 
cosidal  nature,  which  are  insoluble  in  water,  but  which  after  reaching 
the  intestine  are  transformed  by  the  alkaline  secretions,  particularly 
by  the  bile,  into  soluble  and  active  substances.  They  then  excite 
violent  peristalsis  of  the  small  intestine  and  perhaps  also  increase 
secretion,  and  consequently  the  intestinal  contents  are  rapidly  forced 
along  into  the  colon.  As,  however,  these  resins  are  absorbed  or  de- 
stroyed only  after  they  reach  the  large  intestine,  they  cause  increased 
peristalsis  here  also,  with  colic  and  a  resulting  hypergemia  and  reflex 
stimulation  of  the  other  pelvic  organs.  Consequently,  they  are  by  no 
means  so  harmless  as  castor  oil. 

In  this  class  belongs  the  fruit  of  Citrullus  colocynthis,  the 
active  principle  of  which  is  the  exceedingly  bitter  glucoside  colocyn- 
thin,  which  is  soluble  in  water,  and  which  in  small  doses,  1.0-5.0  ( !) 
eg.  of  the  extract  per  dose,  causes  increased  secretion  or  outpouring 
of  fluid  into  the  small  intestine  and  probably  also  in  the  large  intes- 
tine, and  accelerates  the  peristalsis,  while  in  large  doses  it  causes 
vomiting  and  violent  inflammation  of  the  mucous  membrane  of  the 
stomach  and  intestine  (see  p.  192). 

Similar  to  this  is  gamboge,  a  gum  resin  obtained  from  Garcinia 
hanburii,  which,  in  addition  to  gum,  contains  as  its  active  principle 
an  acid  which  in  small  doses  causes  a  watery,  painless  diarrhoea,  and  in 
large  doses  colic  and  gastro-enteritis,  and  at  times  abortion. 

Finally,  mention  should  be  made  of  podophyllin,  a  resin  obtained 
from  Podophyllum  peltatum,  the  active  principle  of  which  is  a  crystal- 
line podophyllotoxin,  which  is  soluble  with  difficulty  in  water.  It  is 
used  in  chronic  constipation  in  doses  of  1.0-5.0  eg.,  and  in  larger  doses 
(0.1  gm.  maximal  single  dose)  as  a  drastic  cathartic,  which,  when 
given  in  too  large  doses,  causes  violent  gastro-enteritis.  Podophyllo- 
toxin and  colocynthin,  even  when  given  subcutaneously,  cause  diar- 
rhoea and  at  times  gastro-enteritis,  and  at  the  same  time  they  cause 
inflammation  of  the  kidneys  and  abscess  at  the  site  of  injection.  They 
are  therefore  unsuitable  for  subcutaneous  administration. 

Euonymin,  a  cathartic  resin  contained  in  Euonymus  atropurpureus,  is 
obtained  as  a  precipitate  on  the  addition  of  water  to  an  alcoholic  extract  of  the 
crude  drug.  After  precipitation  of  euonymin  from  this  solution,  it  still  contains 
a  glucoside  which  acts  not  as  a  cathartic,  but  which  exerts  a  digitalis  action  on 
the  heart  (Romm). 

BIBLIOGRAPHY 

Buchheim  u.  Krich:  Virchow's  Arch.,  1858,  vol.  12. 
Johannes  Miiller:   Diss.,  Dorpat,  1885,  here  literature. 
Magnus,  R.:   Pfliiger's  Arch.,  1908,  vol.  122,  p.  261;  literature  here. 
Meyer,  H.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28,  p.  145;   1897,  vol.  38, 

p.  336. 

Padtberg:   Pfliiger's  Arch.,  1910,  vol.  134,  p.  627. 
Romm:  Diss.,  Dorpat,  1884. 


CATHARTICS  ACTING  ON  LARGE  INTESTINE       207 

III.  CATHARTICS  ACTING  CHIEFLY  ON  THE  LARGE  INTESTINE 

This  group  is  composed  of  a  number  of  drugs  which  all  contain 
anthraquinone  derivatives,  and  particularly  emodin,  a  trioxymethyl 
anthraquinone, 

OH  CH3  OH  CH3 

:o— (    Y>H  f     — co— r 

or 

-co— k    /'  '\   /— co— N 

OH  OH 

and,  in  still  larger  amounts,  substances  which  are  mostly  glucosidal 
in  nature,  and  from  which,  by  hydrolysis  or  oxidation,  different  oxy- 
methyl  anthraquinones  are  formed  in  the  intestine  ( Tschirch x ) .  These 
active  EMODINS  are  formed  by  hydrolytic  cleavage  of  the  glucosides 
of  senna,  rhubarb,  and  the  different  species  of  Frangula,  and  by 
cleavage  and  oxidation  of  certain  constituents  of  aloes. 

The  oxyanthraquinones  possess  the  power  of  electively  exciting 
peristaltic  movements  of  the  large  intestine,  while  they  do  not  appear 
to  produce  any  effect  on  the  small  gut.  Magnus  has  shown  that  they 
exert  their  action  locally  in  the  wall  of  the  large  intestine.  Conse- 
quently, small  doses  cause  only  the  evacuation  of  soft  not  completely 
concentrated  masses  of  faeces,  while  large  doses,  which  cause  a  stormy 
peristalsis  of  the  colon,  produce  profuse  watery  diarrhoea.  In  any 
case  they  produce  their  effect  after  8  hours  or  more, — i.e.,  they  do  not 
act  until  the  drug  lias  passed  from  the  stomach  into-  the  colon.  They 
are  apt  to  produce  more  or  less  violent  colicky  pains  and  tenesmus. 

Among  those  organs  which  may  be  rendered  hypenemic  as  a  result 
of  irritation  of  the  large  intestine  by  drugs,  particularly  when  the 
irritation  and  congestion  are  very  pronounced,  especial  mention  should 
be  made  of  the  female  genital  organs,  which  are  innervated  from  the 
same  nerve  plexus,  and  which  consequently  may  be  reflexly  influenced 
through  the  lower  segments  of  the  intestine.  This  action  may,  accord- 
ing to  the  circumstances,  result  in  a  desirable  or  undesirable  increase 
in  the  menstrual  flow  of  blood,  and  may  also  cause  abortion  in  preg- 
nant patients.  A  number  of  drastic  purgatives  of  this  last-mentioned 
group,  particularly  aloes,  are  consequently  used  and  abused  for  this 
purpose. 

EMODIN  is  in  part  absorbed  and  passes  into  the  urine,  which  may 
then  take  on  a  red  color  on  the  addition  of  an  alkali.  A  certain  por- 
tion is  also  excreted  in  the  milk,  imparting  to  it  a  cathartic  action. 

SENNA  leaves,  obtained  from  Cassia  angustifolia,  contain,  besides 
this  active  glucoside,  a  resin  with  a  very  bitter  taste,  which  may  be 
removed  by  extraction  with  alcohol  without  impairing  the  cathartic 
power  of  the  drug.  From  0.5  to  2.0  gm.  in  the  form  of  an  infusion 
suffice  for  a  mild  cathartic  effect,  while  2.0-5.0  gm.  act  after  5-8  hours 


208  PHARMACOLOGY  OF  THE  DIGESTION 

as  a  powerful  purge.  Senna  leaves  are  the  active  ingredient  of  several 
official  cathartic  preparations,  —  for  example,  the  compound  licorice 
powder  and  the  fluidextract  of  senna. 

Among  the  FRANGULA  species,  Rhanmus  frangula  contains  the 
largest  amount  of  oxymethyl  anthraquinone,  about  5  per  cent.  When 
fresh,  it  contains  emetic  substances  which  disappear  on  keeping,  and 
consequently  this  drug  should  be  at  least  one  year  old. 

The  widely  used  extract  of  cascara  sagrada  is  prepared  from 
Rhamnus  purshiana.  From  the  fruit  of  Rhamnus  cathartica  a  laxa- 
tive syrup  is  prepared. 

RHUBARB,  or  Rheum,  the  root  of  Rheum  officinale,  contains,  besides 
the  cathartic,  oxyanthraquinone  compounds,  a  bitter  and  a  large 
amount  of  tannic  acid,  the  constipating  action  of  which  is  alone  evident 
when  small  doses  —  0.1-0.3  gm.  —  are  given,  but  after  larger  doses  — 
1.0-5.0  gm.  —  the  laxative  action  preponderates. 

ALOE,  OR  ALOES,  the  inspissated  juice  of  the  leaves  of  Aloe  perryi, 
or  socotrine  aloes,  and  of  Aloe  vera,  or  Barbados  aloes,  both  of  which 
are  official  in  the  U.  S.  P.,  contains  about  10-16  per  cent,  of  aloin 
(G'ronewold)  ,  a  golden-yellow  substance  crystallizing  in  needle  form, 
and  considerable  amounts  of  other  anthraquinone  derivatives 
(Tschirch2). 

The  administration  of  from  0.1-0.3  gm.  of  pure  aloin  is  followed 
after  8-10  hours  by  catharsis,  this  effect  occurring  whether  the  drug 
be  administered  internally  or  subcutaneously.  In  the  latter  case  in 
man  it  is  almost  completely  excreted  into  the  large  intestine,  where, 
just  as  after  internal  administration,  it  is  probably  transformed  by 
oxidation  into  a  cathartic  substance.  As  this,  oxidation  is  accelerated 
by  the  presence  of  metal  salts,  particularly  by  that  of  iron  salts,  the 
powerful  cathartic  effects  of  the  pilulas  aloes  et  ferri  are  explained. 
According  to  Elleriberger  and  Baum,  aloes  powerfully  stimulates  the 
secretion  of  bile. 

The  subcutaneous  injection,  best  given  in  a  5-10  per  cent,  solution  in 
formamide,  causes  considerable  pain  lasting  for  several  minutes,  but  otherwise 
appears  to  be  harmless  (H.  Meyer,  Bolster). 

In  the  rabbit  aloes  does  not  act  as  a  cathartic,  and  when  subcutaneously 
injected  it  causes  serious  damage  to  the  kidney  (Brandenberg)  . 

In  addition  to  these  drugs  of  vegetable  origin,  there  are  certain 
synthetically  manufactured  anthracene  derivatives  which  have  proved 
themselves  to  be  useful  cathartics.  The  knowledge  that  phenolphtha- 
lein  acts  as  a  cathartic  is  due  to  an  accidental  observation  made  by 
v.  Vamossy. 

PHENOLPHTHALEIN, 


C6H4(OH)2=C  CO, 


CATHARTICS  ACTING  ON  LARGE  INTESTINE        209 

is  a  yellowish-white  crystalline  powder,  hardly  soluble  in  water,  but 
soluble  in  olive  oil  in  the  proportion  of  about  2  per  cent.  With  alka- 
lies it  forms  red,  readily  soluble  salts,  which,  when  injected  subcu- 
taneously,  cause  violent  irritation  of  the  tissues,  but  which,  when 
administered  intravenously,  are  very  slightly  poisonous.  Phenol- 
phthalein  itself,  when  injected  subcutaneously  dissolved  in  oil,  readily 
causes  evacuation  of  the  bowels  without  causing  local  irritation. 

Phcnoltetrachlorphthalein,  when  injected  subcutaneously  (0.4  gm. 
in  20.0  gm.  of  oil),  acts  much  more  certainly,  and  the  action  persists 
for  a  number  of  days  (Abel  and  Rowntree). 

BIBLIOGRAPHY 

Abel  and  Rowntree:  Journ.  of  Pharmacol.  and  Exp.  Ther.,  1909,  vol.  1,  p.  2. 
Balster:   Dies.,  Marburg,  1890,  here  lit. 
Brandenburg:    Diss.,  Berlin,  1893,  here  lit. 

Ellenberger  u.  Baum:   Arch.  f.  wiss.  u.  prakt.  Tierh.,  1898,  vol.  25,  p.  87. 
Gronewold:  Arch.  d.  Pharm.,  1890,  vol.  228,  p.  115. 

Magnus:   Ergebn.  d.  Physiol.,  1903,  and  Pfltiger's  Arch.,  1908,  vol.  122,  p.  251. 
Meyer,  H.:   Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  28. 

Stierlin:    Miinchn.  med.  Woch.,  1910,  vol.  27.     X-ray  observations  in  man. 
'Tschirch:    Arch.  d.  Pharm.,  vol.  237,  1899;  vol.  238,  1900;  Pharm.  Post,  1904, 

Nos.  17-19,  here  lit. 

"Tschirch:    Schweiz.  Woch.  f.  Chem.  u.  Pharm.,  1904,  vol.  42,  No.  35. 
v.  Vamossy:    Ther.  d.  Gegenw.,  1902,  p.  201. 

SULPHUR. — One  of  those  substances  which  normally  stimulate  the 
peristalsis  of  the  large  intestine  is  sulphuretted  hydrogen  (v.  Bokay}, 
which  is  formed  in  small  amounts  in  the  large  intestine  from  the  cell 
detritus  and  other  substances  containing  sulphur.  The  amount  of 
sulphuretted  hydrogen  formed  here  can  be  markedly  increased  by 
the  administration  of  sulphur,  for  sulphur,  in  finely  divided  form,  is 
reduced  not  only  by  bacteria  but  also  by  the  direct  action  of  certain 
proteids,  particularly  by  the  proteids  present  in  the  mucous  mem- 
brane of  the  large  and  small  intestine  (Heffter),  and  this  reduction 
occurs  both  in  the  acid-reacting  contents  of  the  small  intestine  and  in 
the  alkaline  ones  of  the  large  gut.  On  the  other  hand,  the  gastric 
mucous  membrane  does  not  contain  substances  which  reduce  sulphur. 
Consequently,  when  sulphur  is  administered,  it  is  not  changed  in  the 
stomach  and  produces  no  action  there,  but,  starting  in  the  small 
intestine  and  all  the  way  down  through  the  large  intestine,  it  is  trans- 
formed little  by  little  into  sulphuretted  hydrogen,  which  stimulates 
the  peristalsis. 

As  the  sulphides  of  the  alkalies  have  a  caustic  and  destructive 
action  on  the  tissues,  this  cathartic  effect  was  formerly  attributed 
to  an  irritation  caused  by  them,  but  these  salts  are  not  formed  in  the 
intestine,  as  the  high  carbon  dioxide  tension  of  the  intestinal  contents 
completely  prevents  their  formation.  Consequently,  even  large  doses 
of  sulphur  cause  no  appreciable  caustic  action  or  even,  inflammatory 
irritation  of  the  intestinal  mucous  membrane,  and  hence  no  diarrhoea 
but  only  soft  stools  result  from  its  administration. 
14 


210  PHARMACOLOGY  OF  THE  DIGESTION 

Regensburgcr  observed  intestinal  hemorrhages  in  dogs  to  which  large  doses 
(7.0  gm.)  of  precipitated  sulphur  had  been  administered,  but  it  has  not  yet  been 
determined  whether  these  were  the  result  of  the  caustic  action  of  alkaline 
sulphides  or  were  due  to  mechanical  irritation  produced  by  the  fine  particles 
of  sulphur.  It  is  also  stated  that  sulphur  has  occasionally  occasioned  a  fatal 
gastroenteritis  in  horses,  but  Hartwig,  even  after  administering  to  a  horse 
during  16  days  as  much  as  3.0  kg.  of  sulphur,  was  able  to  produce  only  a  chronic 
sulphuretted  hydrogen  poisoning,  without  any  appreciable  inflammation  of  the 
intestine  ( Frohner ) . 

SULPHURETTED  HYDROGEN. — A  portion  of  the  H2S  whieh  is  formed 
is  absorbed,  and  a  part  of  this  is  oxidized  further,  so  that  the  oxidized 
sulphur  of  the  urine  is  markedly  increased  (Krause)  when  sulphur 
is  ingested.  Another  portion  remains  unchanged,  and  is  excreted 
through  the  lungs  and  the  skin.  It  is  possible  that,  with  the  continued 
us.e  of  sulphur,  certain  mild  symptoms  of  general  H2S  poisoning — 
such  as  headache,  somnolence,  muscular  pains,  and  the  like — may 
occur.  However,  certain  authors  (Wood)  have  attributed  to  the 
exhaled  H2S  a  curative  action  on  the  bronchial  mucous  membranes, 
where  it  perhaps  causes  a  hyperagmia  of  the  smallest  blood-vessels  and 
a  stimulation  of  the  bronchial  secretion.  Those  springs  containing 
sulphuretted  hydrogen  and  alkaline  sulphides  have  the  reputation  of 
being  good  expectorants  and  of  producing  curative  effects  in  pulmonary 
catarrh.  In  veterinary  practice  the  alkaline  sulphides  are  employed 
in  bronchial  diseases. 

In  Metallic  Poisoning. — Sulphuretted  hydrogen  has  also  the  repu- 
tation of  being  useful  in  chronic  metallic  poisonings,  such  as  those 
produced  by  mercury,  lead,  etc.,  and  it  is  possible  that  it  decomposes 
the  compounds  of  these  metals,  which  are  fixed  in  the  tissues  or  which 
are  excreted  into  the  intestine  and  perhaps  reabsorbed,  and  that  it  aids 
in  bringing  about  the  final  elimination  of  these  metals  in  the  form  of 
their  insoluble  sulphides. 

Sulphur  is  non-volatile,  insoluble  in  water,  soluble  in  ether,  fats, 
etc.  Sublimed  sulphur  (flowers  of  sulphur)  is  crystalline,  while 
precipitated  sulphur  (milk  of  sulphur)  is  amorphous  and  forms  a 
very  much  finer  and  consequently  more  active  powder. 

As  Local  Application. — Mixed  with  alkalies  in  pastes  and  salves  it 
forms  alkaline  sulphides,  and  when  these  mixtures  are  applied  to  the 
skin  these  sulphides  dissolve  the  horny  structures,  and  consequently  it 
is  employed  in  the  treatment  of  various  skin  diseases,  such  as  psoriasis, 
pigmentation,  etc. 

Calcium  sulphide,  obtained  by  introducing  H,S  into  lime  water, 
dissolves  the  hairs,  and  consequently  may  be  used  as  a  depilating  agent. 

CARMINATIVES 

Carminative  is  the  name  given  to  a  number  of  substances,  to 
which  are  attributed  the  power  of  relieving  distention, — i.e.,  the  power 
of  driving  along  gases  which  have  collected  in  the  alimentary  canal 
and  which  are  causing  discomfort.  Among  such  are  chamomile 


OBSTIPANTS  211 

flowers  and  fennel  seeds,  which  are  so  often  given  to  little  children, 
and  the  ethereal  oils  obtained  from  these  and  many  other  drugs.  Prob- 
ably these  substances  have  some  power  of  exciting  intestinal  peristalsis, 
but  perhaps  it  is  only  the  mild  local  anaesthestic  action  of  the  ethereal 
oils  which  causes  subjective  relief  of  the  discomfort. 

BIBLIOGRAPHY 

v.  Bokay:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  51,  p.  175. 

Frohner:  Tierarztl.  Arzneimittellehre,  1889,  p.  272. 

Heffter:  Arch.  f.  exp.  Pharm.  u.  Path.,  1904,  vol.  51,  p.  175. 

Krause:   Diss.,  Dorpat,  1853. 

Eegensburger:    Ztschr.  f.  Biol.,  1876,  vol.  12,  p.  479. 

Wood,  H.  C.:  Therap.  Gaz.,  April,  1887,  Detroit,  literature  here. 

OBSTIPANTS,  DRUGS  WHICH  RELIEVE  DIARRHCEA  OR  CAUSE 

CONSTIPATION 

Prom  the  foregoing  it  is  evident  that  drugs  may  produce  consti- 
pation either  by  inhibiting  peristalsis  of  the  stomach  and  of  the  intes- 
tinal secretions.  The  direct  inhibition  of  both  these  processes  by 
opium  or  morphine,  and  under  some  conditions  by  atropine,  has 
already  been  discussed.  Indirectly  they  may  be  inhibited  by  pre- 
venting stimulation  or  irritation  of  the  intestinal  mucous  membrane 
either  mechanically  or  chemically, — i.e.,  primarily  by  withholding 
food,  and  secondarily  by  the  administration  of  slimy  substances  of 
mucilaginous  nature,  such  as  gum  arabic,  decoctions  of  arrow-root, 
marshmallow-root,  etc.,  which  markedly  interfere  with  chemical,  and 
to  some  extent  also  with  mechanical,  irritation  of  the  gastric  and  intes- 
tinal mucous  membranes.  Such  an  effect  is  also  produced  by  the 
secretion  of  a  large  amount  of  a  viscid  mucus,  containing  large 
quantities  of  mucine,  this  being  the  natural  protective  reaction  of  the 
mucous  membrane  when  chemically  irritated. 

If  a  reflex  frog  be  suspended  so  that  the  hind  legs  hang  in  an  acid  solution 
of  just  sufficient  concentration,  the  legs  are  drawn  up  after  a  few  seconds,  but 
if  this  solution  contains  colloid  substances,  such  as  gum  arabic,  gelatin,  or  the 
like,  this  reflex  movement  does  not  occur  at  all,  or  only  very  much  later.  In 
a  similar  fashion  it  is  possible  to  demonstrate,  on  exposed  nerves,  raw  surfaces, 
or  other  irritable  tissues,  the  protective  action  of  slimy  substances  against  chemi- 
cal irritants, — i.e.,  against  the  rapid  penetration  into  the  tissues  of  chemical 
substances  ( Tappeiner ) . 

COLLOIDS,  such  as  thin  paste  of  starch  or  solution  of  vegetable  slime, 
markedly  retard  the  absorption  of  water  and  of  substances,  such  as 
morphine  or  chloral,  in  watery  solution ;  but  they  do  not  cause — and 
in  fact  they  often  check — diarrhoea,  because  peristalsis  is  slowed  and 
consequently  the  fluid  masses  do  not  reach  the  large  intestine. 

Finely  divided  insoluble  substances,  such  as  suspensions  of  talcum* 

*  Debove  (Progres  med.,  1883,  No.  24)  recommends  for  this  purpose  200- 
600  gm.  of  talcum  in  milk. 


212  PHARMACOLOGY  OF  THE  DIGESTION 

creoline  (Stump ft  Garner,  Levy),  or  insoluble  salts,  act  in  a  similar 
fashion,  covering  the  surface  of  the  mucous  membrane  with  a  thin 
coating  and  protecting  it  to  a  certain  degree  against  the  action  of 
chemical  agents. 

CHARCOAL. — Mention  should  here  be  made  of  the  protective  action 
of  finely  powdered  charcoal  (either  animal  or  wood  charcoal)  and  its 
power  of  interfering  with  absorption.  This  substance  possesses  in  a 
very  high  degree  the  power  of  absorbing  substances  dissolved  or  sus- 
pended in  finely  divided  form  in  water,  a  property  which  is  widely 
used  in  chemistry  and  in  technical  manufactures  as  a  means  of 
decolorizing  fluids.  According  to  Wieclwwski,  many  poisons,  such  as 
phenol,  strychnine,  morphine,  bacterial  toxins,  etc.,  are  so  completely 
absorbed  and  persistently  retained  by  charcoal,  when  it  is  taken  in 
sufficient  amounts,  that  these  mixtures  of  poison  and  charcoal  are  abso- 
lutely non-toxic,  either  in  the  alimentary  canal  or  when  injected  sub- 
cutaneously.  In  accordance  with  this,  it  may  be  expected  that  if 
charcoal  (10.0-30.0  gm.  and  more)  be  administered,  it  will  combine 
with  poisons  or  irritating  substances,  or  even  with  bacteria  which  may 
be  present  in  the  alimentary  canal,  and  will  thus  render  them  harm- 
less, particularly  if,  by  the  subsequent  administration  of  a  cathartic, 
the  charcoal  with  its  absorbed  poison  be  rapidly  removed  from  the 
intestine. 

BIBLIOGRAPHY 

Corner:  Miinchn.  med.  Woch.,  1907,  No.  48. 

Levy:   Die  Bolustherapie,  Dies.,  Freiburg,  1908. 

Stumpf:   Ueber  ein  zuverl.  Heilverf.  bei  der  Cholera,  Wiirzburg,  1906. 

Tappeiner:   Miinchn.  med.  Woch.,  1899,  No.  1230,  p.  39;  Arch,  de  pharmacodyn., 

1902,  vol.  10,  p.  67. 
Wiechowski:   Fortschr.  d.  Med.,  1909,  No.  13. 

ASTRINGENTS 

Finally,  the  astringents  act  in  a  similar  but  more  complicated 
fashion.  These  are  substances  which  form  with  the  proteid  constitu- 
ents of  the  cells  and  of  the  secretions  more  or  less  stable  colloid  com- 
pounds, which  are  insoluble  in  neutral  or  weakly  acid  media.  The 
chief  ones  are  the  various  tannic  acids,  certain  metallic  salts,  and 
calcium  hydroxide. 

The  more  viscid  and  less  soluble  these  colloid  compounds  are  the 
more  decidedly  will  they  harden  the  surfaces  on  and  in  which  they  are 
formed,  and  consequently  the  more  effectively  will  they  prevent  their 
own  further  penetration  and  that  of  other  substances  into  the  deeper- 
lying  protoplasms  and  cells. 

They  act  in  a  similar  fashion  to  the  membrane  formed  in  the  wall 
of  a  diffusion  cell  by  precipitation  of  ferrocyanide  of  copper,  which 
renders  these  cells  impermeable  to  substances  in  solution.  Conse- 
quently, with  the  true  astringents  coagulation  and  the  resulting  death 
and  destruction  to  the  protoplasm  are  limited  exclusively  to  the  most 


ASTRINGENTS  213 

superficial  layers  of  the  tissues,  which  are,  as  it  were,  tanned,  and 
which  form  a  protective  coating  against  chemical,  bacterial,  and  even 
against  mechanical  action,  and  thus  protect  against  all  sensory  and 
inflammatory  irritation.  At  the  same  time  the  secretory  activity  of  the 
superficial  glands  which  come  in  contact  with  the  drug  are  diminished 
(Schutz),  and  the  exudation  of  fluid  from  wounds  or  granulation 
tissues  is  stopped. 

Finally,  astringents  also  bring  about  changes  in  the  superficial 
capillaries  and  arterioles,  whose  walls  become  less  permeable  to  the 
plasma  and  leucocytes,  because  the  cement  substance  between  the 
endothelial  cells  is  rendered  less  permeable,  while  at  the  same  time 
the  circular  muscular  fibres  contract  and  the  vessels  are  narrowed 
as  a  result  of  the  coagulation  of  their  proteids  (Heinz).  The  tissues 
consequently  become,  at  least  in  their  most  superficial  layers,  more 
anaemic,  firm,  and  dry,  and  less  sensitive.  These  are  all  effects  which 
counteract  swelling,  redness,  active  secretion,  and  irritability  of  in- 
flamed tissues.  Consequently,  astringents  are  employed  in  inflamed 
wounds  of  mucous  membranes  as  a  means  of  relieving  these  conditions, 
and  particularly  in  the  treatment  of  catarrhal  inflammation  of  the 
gastric  and  intestinal  mucous  membranes. 

Caustic  Actions. — When  astringents  are  at  the  start  applied  in  con- 
centrated solution  to  a  mucous  membrane  or  to  granulation  tissues, 
they  not  only  coagulate  the  most  superficial  layer,  but,  before  the 
protective  layer  has  had  time  to  form,  they  penetrate  deeper  and 
cause  the  destruction  of  the  deeper  tissues.  In  such  case  they  may 
produce  considerable  caustic  effects,  the  degree  and  depth  of  which,  it 
is  clear,  will  depend  on  the  diffusibility  and  solubility  of  the  drug, 
and  also  on  the  chemical  character  of  the  drug  itself  as  well  as  on  that 
of  the  combination  formed  between  it  and  the  constituents  of  the 
tissues.  If  the  eschar  formed  is  not  firm  and  tenacious  but  is  soft  or 
even  fluid,  it  opposes  no  resistance  to  the  further  penetration  and 
deeper  action  of  the  drug.  Consequently,  if  a  caustic  substance 
possesses  a  strong  chemical  avidity  for  the  body  tissues  (with  the 
caustic  metal  salts  it  is  chiefly  the  acid  components  which  exhibit 
such  avidity),  it  may,  even  in  the  low  concentrations,  produce  con- 
siderable destruction  of  the  tissues.  Such  more  extensive  destruction 
and  death  of  the  tissues  will  in  this  case,  as  always,  cause  an  inflam- 
matory reaction,  with  dilatation  of  the  capillaries,  etc.,  which  will 
finally  end  with  the  casting  off  of  the  necrotic  masses  and  the  regenera- 
tion of  new  tissues. 

THE  TANNINS  are  a  number  of  non-nitrogenous  amorphous  colloid 
substances,  present  in  almost  all  plants,  readily  soluble  in  water, 
glycerin,  and  alcohol,  and  entirely  insoluble  in  water-free  ether,  which 
all  possess  the  properties  of  precipitating  albumin,  gelatin,  and  vege- 
table bases  in  neutral  or  weakly  acid  solutions,  and  of  coloring  iron 
salts  dark  blue  or  green.  They  are  weak  acids,  chiefly  anhydrides 


214  PHARMACOLOGY  OF  THE  DIGESTION 

and  condensation  products  of  different  dioxy-  or  trioxybenzoic  acids, 
particularly  of  gallic  acid,  which  is  formed  when  they  undergo  hydro- 
lytic  cleavage  under  the  influence  of  alkalies  or  ferments.  While  gallic 
acid  gives  the  above-mentioned  ink  reaction  with  iron  salts,  it  pre- 
cipitates neither  albumin  nor  gelatin,  and  consequently  is  without 
astringent  action. 

TANNIN,  or  TANNIC  ACID,  is  a  yellowish  powder  obtained  from  nut- 
galls.  It  possesses  an  astringent  taste  and  acts  as  an  astringent  in  the 
above-described  fashion,  and,  under  certain  conditions,  may  produce 
a  superficial  caustic  effect.  It  may  be  used  as  an  astringent  appli- 
cation to  all  accessible  mucous  membranes  or  granulating  surfaces, — 
for  example,  as  a  gargle  or  local  application,  in  %-l  per  cent,  solu- 
tion, in  inflammation  of  the  throat. 

Action  in,  Alimentary  Canal. — It  is  not  well  adapted  for  oral 
administration  in  the  treatment  of  intestinal  catarrh,  because  it 
produces  its  astringent  effects  chiefly  on  those  tissues  with  which  it 
first  comes  in  contact, — namely,  the  gastric  and  duodenal  mucous 
membranes, — and  thus  disturbs  the  appetite  and  digestion,  and  be- 
cause in  the  small  intestine  it  undergoes  hydrolytic  cleavage  and 
absorption,  and  consequently  does  not  pass  far  enough  down  in  the  gut. 

Reputed  Action  after  Absorption. — Gallic  acid  after  absorption  is  almost 
completely  combusted,  but  a  small  portion  is  excreted  in  the  urine,  either  unaltered 
or  in  conjugation  with  sulphuric  acid  (Morner).  Tannic  acid  itself  or  as  an 
alkaline  tannate  does  not  pass  into  the  urine;  this  is  quite  evident  from  the  fact 
that  any  human  urine  which  contains  no  albumin,  whether  acid  or  alkaline, 
forms  an  insoluble  precipitate  with  tannic  acid,  even  in  the  proportions  of 
1:  100,000.  This  same  precipitate  is  also  formed  on  the  addition  of  tannin  to 
the  clear  urine  which  is  passed  after  ingestion  of  tannin  (Rost1).  From  these 
facts  it  is  probable  that,  during  or  before  its  absorption  by  the  intestinal 
mucosa,  tannic  acid  is  completely  transformed  into  gallates  of  the  alkalies, 
which  possess  no  astringent  properties.  Consequently,  an  astringent  or  styptic 
effect  in  the  lungs,  kidneys,  etc.,  cannot  result  from  the  oral  or  any  other 
administration  of  tannin. 

Drugs  Containing  Tannin. — When  it  is  desirable  that  tannic  acid 
reach  the  lower  portions  of  the  intestine,  drugs  are  used  which  contain 
tannin  inclosed  in  cellulose  or  in  mucilaginous  or  other  substances 
which  protect  it  from  too  rapid  solution  and  absorption.  Such  drugs 
as  rhatany,  krameria,  quercus  alba,  kino,  etc.,  in  the  form  of  their 
extracts  or  decoctions,  fulfil  this  indication. 

The  large  amounts  of  tannin  present  in  many  drugs  which  are  used  for 
quite  different  indications  often  produce  undesirable  effects,  as  is  the  case  with 
extracts  of  calisaya  or  pomegranate-root  bark.  Radix  ipecacuanhse,  which  we 
have  already  studied  in  the  section  on  emetics,  also  contains  large  amounts  of 
tannic  acid,  and  it  is  probable  that  it  is  for  this  reason  that  it  is  used  in  the 
treatment  of-  dysentery  [? — see  p.  182. — TB.] 

TANNIC  ACID  COMPOUNDS. — The  desirable  effects,  however,  are 
much  more  certainly  and  completely  obtained  by  the  administration 
of  synthetically  manufactured  tannic  acid  compounds  in  which  the 
tannic  acid  is  firmly  combined.  These  are  almost  tasteless  powders, 


ASTRINGENTS  215 

which  produce  no  astringent  effects  in  the  mouth  or  in  the  stomach, 
but  which  are  gradually  dissolved  in  the  alkaline  intestinal  juices, 
with  the  liberation  of  tannin  in  an  active  form. 

Tannalbin  is  such  a  compound,  and  is  a  tannin  albuminate  con- 
taining about  50  per  cent,  of  tannic  acid,  which  is  rendered  resistant 
to  gastric  digestion  by  heating  to  110-120°  C.  (Gottlieb).  This  is 
gradually  broken  up  by  the  pancreatic  juice,  and  consequently  exerts 
its  action  throughout  the  alimentary  canal  as  far  down  as  the  colon 
and  rectum.  Its  dosage  is  1.0-2.0  gm.  several  times  daily. 

Tannigen. — Another  is  tannigen,  or  diacetyl  tannin,  a  yellowish- 
gray  powder  insoluble  in  neutral  and  acid  fluids,  with  a  mild  acid 
taste,  which  contains  about  85  per  cent,  of  tannin.  It  is  dissolved  by 
weak  alkalies,  such  as  the  carbonates,  borates,  etc.,  and,  in  such  solu- 
tions, precipitates  albuminates  and  gelatin.  When  given  in  rather 
large  doses  (0.5-4.0  gm.),  it  passes  through  the  bowel  down  into  the 
large  intestine,  where  it  may  be  found  in  part  as  unchanged  tannigen 
but  in  part  in  the  form  of  tannie  acid  (H.  Meyer  u.  F.  Mutter,  Bost 2) . 

Tannocol,  a  compound  of  tannic  acid  with  gelatin,  containing  about 
45  per  cent,  of  tannin,  and  tannoform,  a  condensation  product  of  tan- 
nin and  formaldehyde,  are  substances  with  the  same  general  properties. 

Goto. — In  this  connection  mention  may  be  made  of  coto-bark  decoctions, 
which  are  employed,  particularly  in  Italy,  as  curative  agents  in  diarrhoea.  The 
active  constituents  of  this  bark  is  not  a  tannin,  but  a  very  irritant  bitter, 
cotoin,  which  is  employed  in  doses  ranging  from  5.0-50.0  mg.  Very  little  is 
known  concerning  its  action  on  the  intestinal  mucous  membrane. 

BIBLIOGRAPHY 

Gottlieb:  Deut.  med.  Woch.,  1896.  No.  11. 

Heinz:  Virchow's  Arch.,  1889,  vol.  116. 

Meyer,  H.,  u.  F.  Miiller:  Deut.  med.  Woch.,  1894,  No.  31. 

Morner:  Ztschr.  f.  phys.  Chem.,  1892,  vol.  16,  p.  255. 

'Rost:    Sitz.-Ber.  Ges.  Bef.  d.  ges.  Naturw.  Marburg,  March,  1898. 

*Rost:    Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  346. 

Schutz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27. 

METALLIC  SALTS 

Of  the  astringent  metallic  salts  only  those  are  suitable  for  the 
treatment  of  inflammation  of  the  gastric  and  intestinal  mucous 
membranes  which  neither  cause  vomiting  nor  readily  produce  caustic 
effects  on  the  mucous  membranes.  These  requirements  are  best  met 
by  the  insoluble 

BISMUTH  SUBNITRATE,  the  dose  of  which  is  0.2-1.0  gm.  or  more 
several  times  a  day.  It  forms  on  the  mucous  membrane  a  firmly 
adhering  coating  (  ?  TR.  ) ,  toughening  and  protecting  it  and  diminish- 
ing its  secretory  activity.  Unless  the  mucous  membrane  is  eroded, 
bismuth  subnitrate  is  not  absorbed,  and  consequently  as  large  amounts 
as  one  desires  may  be  given  without  danger  of  poisoning  by  absorp- 
tion of  the  metal.  This  salt  is  to-day  often  used  by  rontgenologists 


216  PHARMACOLOGY  OF  THE  DIGESTION 

for  the  purpose  of  observing  or  photographing  the  stomach  and  intes- 
tine and  their  movements. 

Danger  of  Nitrite  Poisoning. — However,  such  employment  carries 
with  it  some  danger  from  another  source,  for  abnormally  active  bac- 
terial fermentation  in  the  large  intestine  reduces  the  nitrate  to  a 
nitrite,  which  may  be  absorbed  in  considerable  amounts.  As  nitrites 
are  poisons  to  the  blood,  very  small  amounts  of  which  may  cause 
death,  this  danger  should  be  avoided,  and,  consequently,  in  rontgeno- 
logic work  the  basic  bismuth  sulphate  or  chloride  or  oxide  should  be 
substituted  for  the  subnitrate. 

Cattle  and  deer  may  suffer  from  the  same  toxic  action  on  the  blood  if  they 
consume  considerable  amounts  of  saltpetre  spread  upon  the  fields  as  a  fertilizing 
agent.  If  sodium  nitrate  is  not  rapidly  absorbed,  but  remains  for  a  considerable 
time  in  the  stomach,  it  may  be  reduced  and  transformed  into  a  lethal  poison 
(Bohme,  E.  Meyer,  Hoffmann  u.  Bennecke). 

In  the  large  intestine  bismuth  subnitrate  and  other  bismuth  salts 
combine  with  H2S  and  form  the  deep-black  bismuth  sulphide,  and  in 
this  fashion  one  of  the  effective  stimuli  of  peristalsis  is  removed  and 
consequently  peristalsis  becomes  less  active  (v.  Bokay). 

Other  basic  insoluble  bismuth  compounds  used  in  medicine  in  the 
same  fashion  as  the  subnitrate  are  the  subgallate  and  subsalicylate, 
the  former  of  which  carries  the  commercial  name  of  dermatol. 

LEAD  ACETATE,  or  sugar  of  lead,  is  soluble  in  water,  and  conse- 
quently should  be  employed  only  in  weak  non-corroding  concentrations. 
The  dose  is  0.1  gm.  ( !)  per  dose,  0.3  gm.  ( !)  per  diem.  It  is  a  power- 
ful astringent,  constricting  the  vessels  quite  markedly,  and  is  slowly 
absorbed,  and,  therefore,  when  used  for  a  long  time  may  cause  poison- 
ing. This  salt  could  be  entirely  dispensed  with  for  internal  use,  and 
the  same  is  true  of 

ALUM,  which,  although  a  good  astringent  and  one  which  when 
absorbed  does  not  cause  any  poisoning,  readily  causes  gastric  irri- 
tation or  vomiting,  even  when  administered  in  small  amounts. 

SILVER  NITRATE  has  also  been  much  used  as  an  astringent  in  the 
stomach  and  intestine.  As  a  large  part  of  it  is  changed  in  the  stomach 
into  silver  chloride,  which  is  insoluble  in  water  containing  hydrochloric 
acid,  but  which  is  somewhat  soluble  in  the  presence  of  chlorides  of  the 
alkalies,  it  is  probably  entirely  ineffective  in  the  stomach.  [With  this 
sweeping  statement  clinicians  will  hardy  agree. — TR.]  When  adminis- 
tered by  mouth,  however,  there  can  be  little  doubt  that  silver  nitrate 
never  reaches  the  lower  portion  of  the  intestine  in  an  active  form,  for 
it  is  rapidly  reduced  to  metallic  silver  by  organic  substances  present 
in  the  stomach  and  intestine. 

A  small  portion  is  absorbed  probably  as  an  albuminate  and  dis- 
tributed throughout  the  body  by  the  lymph,  where  it  is  deposited  in 
the  various  tissues  in  the  form  of  a  reduced  metal  (Fraschetti) .  In 
this  fashion  the  various  organs — and,  in  man,  especially  the  skin — 


LIME  WATER  217 

are  colored  slate-gray,   from  which   in   other   particulars   no   harm 
results.    This  condition  is  known  as  argyria. 

CALCIUM  HYDROXIDE,  chiefly  used  as  lime  water,  which  contains 
0.15  per  cent,  of  Ca(OH)2,  forms  insoluble  soaps  with  the  fatty  acids, 
and  thus  toughens  the  lipoid  constituents  and  the  intercellular  cement 
substances  of  the  tissues,  an  action  which  may  be  aided  by  the  mechani- 
cal protective  action  of  the  calcium  carbonate  which  is  formed  on  the 
surface  of  the  mucous  membranes.  The  very  slight  concentration 
of  lime  water  renders  it  impossible  for  it  to  cause  any  corrosive  effect, 
while  its  alkaline  nature  enables  it  to  dissolve  the  tenacious  mucus 
adhering  to  the  inflamed  mucous  membranes  and  thus  to  produce  a 
cleansing  effect  (HarnacJc).  As  an  alkali,  it  can  also  neutralize  harm- 
ful acids,  such  as  are  formed  in  the  acid  intestinal  catarrh  of  nursing 
infants  (Baudnitz).  The  constipating  effects  of  lime  water  or  of 
waters  containing  calcium  are  probably  also  due  in  part  to  the  action 
exerted  by  the  lime  salts,  after  their  absorption  on  the  vegetative  ner- 
vous system,  the  excitability  of  which  they  depress,  and  in  part  to  their 
effects  on  the  capillary  vessels,  the  permeability  of  which  they  lessen 
(Chiari  u.  Frohlich,  Chiari  u.  Januschke)  (see  p.  495). 

BIBLIOGRAPHY 

Baudnitz:  Prager  med.  Woch.,  1893,  No.  29. 

Bohme:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  57,  p.  441. 

v.  Bokay:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol  23,  p.  209. 

Chiari  u.  Frohlich:  Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  64,  p.  214. 

Chiari  u.  Januschke:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  65,  p.  120. 

Fraschetti:    Moleschott's  Unters.,  1895,  vol.  15,  p.  143. 

Harnack:  Berl.  klin.  Woch.,  1888,  No.  18;  1889,  No.  26. 

Meyer,  E.:  Miinchn.  med.  Woch.,  1906,  No.  53. 


CHAPTER  VII 

PHARMACOLOGY  OF  THE  REPRODUCTIVE  ORGANS 

NERVOUS   AND    CHEMICAL    CORRELATION 

LIKE  those  of  the  alimentary  canal,  the  functions  of  the  genital 
organs,  with  their  glands  and  unstriated  muscles,  are  controlled  partly 
by  manifold  nervous  reflexes  and  partly  by  the  direct  action  of 
various  stimulating  substances  which  reach  them  in  the  blood  stream. 
While  formerly  the  relationship  between  the  different  functions  of  the 
genital  organs  with  each  other  and  with  numerous  other  functions 
were  attributed  exclusively  to  central  nervous  influences,  it  has  more 
recently  been  proved  that  the  genital  organs  influence  the  development 
and  function  of  distant  tissues  and  organs  chiefly  by  means  of  their 
internal  secretions, — i.e.,  by  chemical  agents  (hormones). 

The  Ovaries. — Thus,  the  importance  of  the  ovaries  for  the  development  of 
the  other  female  sexual  organs  is  well  known.  In  animal  experiments,  after 
extirpation  of  the  ovaries  in  young  subjects  the  uterus  and  tubes  remain  rudi- 
mentary (Hegar,  Kehrer),  but,  if  the  ovaries  are  transplanted  under  the  skin, 
normal  development  of  the  uterus  and  tubes  occurs  (Halban).  The  connection 
between  the  periodic  changes,  which  the  uterine  mucous  membrane  undergoes, 
and  the  associated  changes  in  numerous  bodily  functions,  are  also,  at  least  in 
part,  due  to  the  action  of  chemical  substances  which  are  formed  as  the  ovum 
matures,  for  Knauer  observed  the  occurrence  of  "heat"  in  animals  in  which 
the  ovaries  had  been  transplanted  to  other  parts  of  the  peritoneal  cavity. 

BOTH  THE  TESTICLES  AND  THE  OVARIES  form  chemical  substances, 
which  exert  an  influence  on  other  portions  of  the  genital  system  and 
on  many  other  parts  of  the  body.  This  highly  specialized  tissue  is 
very  readily  destroyed  by  the  action  of  X-rays,  so  that  the  application 
of  these  rays  leads  to  atrophy  of  testicles  or  ovaries,  and  thus  to  all 
the  indirect  results  of  a  cessation  of  the  function  of  these  organs. 
In  practice  the  ovaries  are  at  times  thus  treated.  The  ovarian  follicles 
appear  to  be  very  susceptible  also  to  certain  toxic  substances  at  times 
present  in  the  blood,  so  that,  for  example,  sterility  and  retrogression 
of  the  pregnancy  may  be  produced  by  injections  of  choline  (v.  Hippel 
and  Pagenstecher) . 

It  is  this  more  or  less  sudden  cessation  of  the  ovarian  influences 
which  causes  the  manifold  disturbances  following  ovariotomy  and 
the  menopause.  Reliable  observations  indicate  that  they  may  be 
favorably  influenced  by  the  internal  administration  of  ovarian  tissue 
(Chrobak,  Landau}. 

Other  functions  connected  with  the  function  of  reproduction,  as 
well  as  those  of  the  reproductive  organs,  are  also  influenced  by  the 
internal  secretion  of  the  germ-glands.  Examples  of  this  are  as  fol- 
lows :  The  callosities  on  the  thumb  and  certain  muscles  of  the  forearm 
218 


NERVOUS  AND  CHEMICAL  CORRELATION  219 

of  the  brown  frog  hypertrophy  at  the  rutting  season.  This  does  not 
occur  in  castrated  frogs  if  a  piece  of  testicle  is  put  into  the  dorsal 
lymph-sac  and  gradually  absorbed  (Niissbaum] .  The  complete  de- 
velopment of  all  the  secondary  sexual  characteristics  is  also  influenced 
by  the  germ-cells,  as  are  the  growth  of  bone  and  the  general  metabo- 
lism. As  far  as  the  effect's  of  these  internal  secretions  on  other  func- 
tions are  definitely  known,  they  will  be  discussed  elsewhere,  but  we 
are  far  from  possessing  anything  like  a  complete  knowledge  of  the 
internal  secretions  or  of  their  actions.  For  this  reason,  their  thera- 
peutic employment  with  dear  indications  is  at  the  present  time  ex- 
tremely limited. 

BIBLIOGRAPHY 

Chrobak:   Zentralbl.  f.  Gyn.,  1896,  vol.  20. 

Halban:   Monatsschr.  f.  Geburtsh.  u.  Gyn.,  1901,  vol.  12,  p.  496. 

Hegar:   Beitr.  z.  Geburtsh.  u.  Gynakol.,  1903,  vol.  7,  p.  201. 

v.  Hippel  u.  Pagenstecher :   Miinchn.  med.  Woch.,  1907,  No.  10. 

Knauer:  Arch.  f.  Gyn.,  1900,  vol.  60,  p.  322. 

Landau,  M.:   Berl.  med.  Woch.,  1896. 

Nussbaum:   Pfluger's  Arch.,   1909,  vol.   129,  p.   110. 

ERECTION. — Among  the  secondary  sexual  characteristics  which  first 
become  evident  at  puberty,  and  which  depend  on  the  internal  secre- 
tions of  the  testicles,  is  the  development  of  a  specific  sensibility  of 
certain  lower  nervous  centres,  which  are  involved  in  the  function  of 
reproduction.  The  complicated  reflexes  which  induce  erection  are 
primarily  dependent  on  psychic  processes,  and  may  be  excited  or  in- 
hibited from  the  cerebral  cortex,  or  may,  on  the  other  hand,  result 
from  peripheral  stimuli. 

YOHIMBIN,  an  alkaloid  contained  in  the  yohimbe  bark  (W.  Africa), 
apparently  is  able  to  increase  the  excitability  of  the  centres  for  erec- 
tion in  the  lumbar  cord,  even  in  doses  which  do  not  affect  the  excita- 
bility of  other  centres  there,  such  as  that  for  the  patella  reflex  (Fr. 
Muller).  At  the  same  time  it  causes  a  local  dilatation  (by  direct 
action  on  the  vessel  walls)  in  various  vascular  systems,  but  most  espe- 
cially so  in  the  vessels  of  the  penis,  and  there  results  a  marked  increase 
in  the  amount  of  blood  flowing  out  of  the  dorsal  vein  of  the  penis. 
It  is  probable  that  other  reputed  aphrodisiacs  favor  erection  by  local 
vasodilating  actions.  The  aphrodisiac  effects  of  cantharidin  and  cer- 
tain other  drugs,  which  are  excreted  by  the  kidney  and  set  up  an 
inflammatory  irritation  of  the  urogenital  tract,  are  probably  due  to 
such  sensory  irritation  and  its  accompanying  vasodilatation. 

MAMMARY  GLANDS 

A  most  interesting  nervous  and  chemical  correlation  exists  between 
te  genital  system  and  the  function  of  the  mammary  glands,   the 
>wth  of  which  in  the  female  at  puberty  is  doubtless  due  to  a  stimulus 
.ing  from  the  ovaries. 


220       PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

Observations  on  animals  have  shown  that  the  development  of  these 
glands  is  retarded  after  double  oophorectomy,  but  proceeds  quite  nor- 
mally after  successful  transplantation  (Foges,  Kramer}.  The  changes 
in  the  breast  during  pregnancy  also  occur  independently  of  any  ner- 
vous influences,  for  after  successful  transplantation  of  these  glands 
their  growth  and  active  secretion  have  been  observed  in  pregnant 
guinea-pigs  (Ribbert).  The  hormone  here  appears  to  be  a  product 
of  the  fetal  metabolism,  for  injections  of  fetal  extracts  excite  hyper- 
trophy of  the  mammary  gland  in  virgin  animals  (Starling  and 
Claypon,  Foa,  Biedl). 

LACTAGOGUES. — The  inauguration  of  the  lacteal  secretion  after 
delivery  is  likewise  in  part  due  to  chemical  stimuli,  and  apparently 
also  in  part  to  the  cessation  of  an  inhibitory  influence  which  is  exerted 
by  the  fetal  substances  which  stimulate  the  growth  of  these  glands 
(D'Errico).  Very  recently  several  investigators  (Basch,  Lederer 
and  Pribram)  have  demonstrated  the  presence  of  galactagogue  sub- 
stances in  placental  extracts,  injection  of  which  increases  the  milk 
secretion  of  goats. 

This  secretion,  moreover,  may  be  influenced  by  numerous  nervous 
influences,  and  especially  by  manifold  reflexes,  among  which  those 
from  the  genital  organs  and  that  from  suckling  are  especially  impor- 
tant. The  innervation  of  the  lacteal  glands  must,  however,  be  entirely 
different  from  that  of  the  other  true  glands,  for  even  such  a  typical 
stimulant  of  glandular  activity  as  pilocarpine  produces  no  effect  on 
the  milk  secretion  (Hammerbacher) .  While,  generally  speaking,  this 
secretion  depends  on  the  general  state  of  nutrition,  it  can  in  no  way 
be  influenced  by  feeding  special  food-stuffs,  nor  has  it  been  proved  that 
it  can  be  influenced  by  pharmacological  agents.  Of  true  medicinal 
galactagogues  there  are  none,  but,  on  the  other  hand,  it  is  claimed  that 
the  secretion  of  milk  may  be  distinctly  lessened  by  the  administration 
of  KI. 

ELIMINATION  OF  DRUGS  IN  THE  MILK. — That  many  foreign  substances  may 
pass  into  the  milk  has  been  definitely  established,  the  following  having  been 
demonstrated  in  human  milk  after  their  medicinal  administration:  iodine,  bro- 
mine, salicylic  acid,  antipyrine,  arsenic,  and  mercury  (Bucura),  while  alcohol, 
morphine,  and  atropine  have  been  found  in  the  milk  of  animals.  However,  only 
very  small  amounts  of  such  foreign  substances  are  present  in  the  milk. 

The  excretion  of  antitoxins  through  the  lacteal  glands  (Ehrlich) 
appears  to  be  of  great  significance  in  connection  with  the  transference 
of  protective  substances  to  the  suckling. 

BIBLIOGRAPHY. 

Basch:  Monatsh.  f.  Kinderheilkunde,  1909,  vol.  8. 

Biedl:   Innere  Sekretion,  1910,  p.  343. 

Bucura:  Zeitschr.  f.  exp.  Path.  u.  Ther.,  1907,  vol.  4,  p.  398. 

Ehrlich:  Zeitschr.  f.  Hyg.  u.  infektionskrankh.,  1892,  vol.  12. 

D'Errico:  La  Pediatria.  1910,  No.  4. 

Foa:   Arch,  di  Fisiol.,  1909,  vol.  5. 


UTERINE  MOVEMENTS 


Foges:  Zentralbl.  f.  Physiol.,  1905,  vol.  19,  p.  233. 
Hammerbacher :   Pfliiger's  Arch.,  1884,  vol.  33,  p.  228. 
Kramer:   Miinchn.  med.  Woch.,  1906,  No.  39;   1909,  No.  30. 
Lederer  u.  Pribram:   Pfltiger's  Arch.,  1910,  vol.  134,  p.  531. 
Miiller,  Fr.:  Arch,  intern,  de  pharm.  et  de  th6r.,  1907,  vol.  17,  p.  81. 
Ribbert:    Fortschritte  d.  Medizin,  1898,  vol.  7. 

Starling  and  Claypon:  Proc.  of  the  R.  S.,  1905,  p.  505;  Ergebnisse  d.  Physiol., 
1906,  pp.  6-64. 

THE  PHARMACOLOGY  OF  THE  UTERINE  MOVEMENTS 

Although  the  same  pharmacological  principles  hold  good  for  the 
treatment  of  disease  of  the  mucous  membranes  of  the  genital  tract  as 


Bladder 

IJypogaatric  plexus 
.  16. — Sympathetic  nerves,  red ;  nervus  hypogastricus,  blue. 

for  the  other  mucous  membranes  (see  Pharmacology  of  Inflammation, 
p.  48.1,  and  Disinfection  of  the  Mucous  Membranes,  p.  508) ,  the  pharma- 
cology of  the  uterine  movements  deserves  special  attention. 

Like  the  intestine,  the  uterus  in  situ  or  when  isolated  manifests 
)endulum  movements  and  peristaltic  contractions,  and  these  phe- 
lomena  may  be  studied  for  hours  in  the  perfused  uterus  (Kurdinow- 
"  or  in  one  surviving  in  Ringer's  solution  which  is  kept  saturated 


222       PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

with  oxygen  (Kehrer1)-).  It  is  thus  evident  that  this  organ'  contains 
within  itself  the  factors  necessary  for  its  automatic  contractions, 
which  vary  according  to  the  state  of  the  uterus,  occurring  most  fre- 
quently in  the  early  stages  of  pregnancy,  and  later  becoming  less  fre- 
quent but  more  powerful,  being  separated  by  long  periods  of  inactivity. 

INNERVATION. — The  uterine  movements,  like  those  of  other  organs  contain- 
ing smooth  muscle,  are  regulated  by  the  central  nervous  system,  receiving  from 
it  motor  and  inhibitory  impulses  through  the  sympathetic  and  probably  also 
through  the  sacral  autonomic  nerves  (see  Fig.  16).  The  Nervus  pelvicus 
(erigens),  whose  fibres  arise  from  the  second,  third,  and  fourth  sacral  roots, 
supplies  the  rectum,  anus,  bladder,  and  the  external  genitals,  and  probably  also 
the  uterus,  with  sacral  autonomic  fibres,  while  the  hypogastric  nerve,  which 
arises  from  the  inferior  mesenteric  ganglion,  and  the  spermatic  nerve,  from  the 
spermatic  ganglion,  belong  to  the  true  sympathetic  system  proper.  The  uterine 
ganglion  lies  more  peripherally  in  the  neighborhood  of  the  cervix.  Much  uncer- 
tainty still  prevails  as  to  the  influence  exerted  on  the  uterus  by  these  different 
nerves,  for  not  only  is  the  anatomical  arrangement  complicated,  but,  in  addition, 
their  different  behavior  in  different  species  renders  it  most  difficult  to  determine 
definitely  their  physiological  significance. 

EFFECTS  OF  EPINEPHRIN  AND  OF  STIMULATION  OF  THE  SYMPATHETIC. 
— According  to  Langley  and  Anderson,  in  the  cat  stimulation  of  the 
hypogastric  at  first  produces  chiefly  stimulation  of  the  inhibitory 
fibres,  while  in  the  rabbit  it  causes  excitation  from  the  start.  Epi- 
nephrin  acts  on  the  uterus  quite  analogously  to  the  stimulation  of 
these  sympathetic  fibres,  causing  in  the  cat  first  inhibition  and  then 
excitation,  but  in  the  rabbit  immediate  excitation. 

EFFECTS  OF  ' '  AUTONOMIC  ' '  DRUGS  AND  OF  STIMULATION  OF  AUTONO- 
MIC NERVES. — The  influence  of  the  nervus  pelvicus  is  still  more  uncer- 
tain, for  this  nerve  carries  vasodilating  nerves  to  the  uterus  (v.  Basch 
and  Hofmann),  and  stimulation  of  its  trunk  excites  uterine  contrac- 
tions (Rb'hrig,  F.  Kehrer),  which  last  effect,  according  to  Langley  and 
Anderson,  is  due  only  to  its  containing  some  fibres  from  the  hypo- 
gastricus,  which  join  it  deep  down  in  the  pelvis.  Pharmacological 
observations,  however,  indicate  that  the  pelvic  nerve  also  contains 
•motor  nerves,  which  actually  come  from  the  sacral  autonomic  system, 
for  that  group  of  drugs  which  in  general  act  on  the  autonomic  nerve- 
endings  produce  a  decided  effect  on  the  uterus.  Thus,  pilocarpinc 
and  physostigmine  excite  violent  uterine  contractions,  which  may 
become  tonic  in  character,  while  here,  as  in  the  intestine,  atr opine 
in  small  doses  causes  excitation  and  in  large  doses  cessation  of  the 
movements  of  the  uterus  (E.  Kehrer1*2). 

DIFFERENT  REACTION  OF  THE  GRAVID  AND  NON-GRAVID  UTERUS 

NICOTINE  produces  different  effects  in  different  species  of  animals, 
and  also  in  the  gravid  and  non-gravid  uterus,  primarily  inhibiting 
and  later  exciting  the  empty  organ  and  immediately  exciting  the 
gravid  on©.  Epinephrin,  too,  exhibits  a  similar  difference  in  the 
effects  produced  by  it  in  the  gravid  and  non-gravid  uterus 


UTERINE  MOVEMENTS  223 

(Dale,  E.  Kehrcr1,-).  The  difference  in  the  reactions  of  the 
gravid  and  non-gravid  uterus  to  these  drugs  is  in  accord  with 
the  influence  of  sympathetic  stimulation  in  the  two  conditions 
for  it  has  been  found  that  in  the  cat  stimulation  of  the  hypogastric 
nerve  inhibits  the  non-pregnant  uterus  but  excites  the  pregnant  one 
(Langley  and  Anderson,  Dale).  It  would,  therefore,  appear  that 
the  stretched  muscle-fibres  of  the  gravid  uterus  are  more  susceptible 
to  all  exciting  agents  than  those  of  the  empty  organ  (Cushny).  This 
is  in  accord  with  clinical  experience. 

HYPOPHYSIS  EXTRACTS. — Recently  it  has  been  found  that  the 
extract  made  from  the  infundibular  portion  of  the  hypophysis,  pitui- 
trin,  excites  maximal  contraction  of  the  rabbit's  uterine  muscle  and 
renders  it  more  susceptible  to  motor  stimuli  (Frankl-Hochwart  and 
Frohlich). 

PILOCARPINE  AND  NICOTINE. — The  above-discussed  action  of  pilo- 
carpine  is  the  ground  for  its  employment  as  an  oxytoxic  (Brennecke, 
Kleinwdchter) ,  while  the  excitation  of  the  uterine  contractions  pro- 
duced by  nicotine  is  of  toxicological  interest  on  account  of  the  occa- 
sional unjustifiable  employment  of  an  infusion  of  tobacco  as  an 
abortifacient.  Besides  those  already  mentioned,  numerous  other  drugs 
act  on  the  terminal  nervous  mechanism  in  the  uterus.  Among  these 
is  quinine,  which  is  much  used  to  strengthen  lagging  pains  (Backer, 
Mdurer,  Conitzer),  excites  contractions  in  the  surviving  uterus  and 
hence  must  act  peripherally  (Kurdinowski,2  E.  Kehrer3).  Small 
doses  of  morphine  excite  (while  large  ones  inhibit)  uterine  contractions 
(E.  Kehrer4).  Bearing  in  mind  the  difference  in  individual  suscepti- 
bility to  morphine,  this  difference  in  the  effects  of  small  and  large 
doses  accounts  for  the  contradictory  clinical  views  concerning  the 
effect  of  morphine  on  parturition.  In  this  connection  it  is  of  interest 
that  scopolamine  appears  not  to  affect  the  uterine  contractions 
appreciably. 


" 

s 


In  addition  to  being  affected  by  these  peripherally  acting  agents, 
e  uterine  contractions  may  be  influenced  by  many  agents  which  act 

the  central  nervous  system  (centres  in  the  lumbar  cord),  as,  for 
example,  by  anaemia  or  asphyxia,  both  of  which  strengthen  the  con- 
tractions. These  spinal  centres  are,  moreover,  under  the  control  of 
higher  centres,  some  of  which  are  situated  in  the  cerebral  cortex  and 
may  be  influenced  by  reflexes  of  the  most  varied  origin,  especially  from 
the  nasal  mucous  membrane  (Fliess,  Schiff).  Toxicologically  it  is 
important  to  remember  that,  simultaneously  with  peristalsis,  uterine 
contractions  may  be  reflexly  excited  by  chemical  irritation  of  the 
intestinal  mucous  membrane  (E.  Kehrer*).  It  is  for  this  reason  that 
drastic  purgatives — for  example,  aloes — may  excite  uterine  contrac- 


224       PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

tions  and  cause  abortion,  not  only  by  causing  hypergemia  of  the  pelvic 
organs  but  also  by  causing  reflex  stimulation  of  the  uterine  contrac- 
tions. The  same  holds  for  other  abortifacients,  such  as  the  ethereal 
oils  of  Tanacetum  vulgare  (tansy),  Thuja  occidentalis  (arbor  vitce), 
Taxus  baccata  (yew  tree),  Juniperus  sabina,  etc.,  which  all  cause 
gastro-enteritis  and  at  the  same  time  may  cause  abortion.  The  extent 
to  which  specific  effects  on  the  uterus  also  contribute  to  this  result 
has  not  yet  been  settled.  Why  uterine  hemorrhages,  abortions,  and 
miscarriages  occur  after  large  doses  of  salicylic  acid  is  entirely 
unknown  (Binz}. 

BIBLIOGRAPHY 

Backer:  Dcut.  med.  Woch.,  1905,  p.  417. 

v.  Basch  u.  Hofmann:  Wiener  med.  Jahrbiicher,  1877,  p.  465. 

Binz:   Berl.  klin.  Woch.,  1893,  p.  985. 

Brennecke:  Berl.  klin.  Woch.,  1880,  p.  122. 

Conitzer:  Arch.  f.  Gyn.,  1907,  vol.  82,  p.  349. 

Cushny:   Journ.  of  Physiol.,  1906,  vol.  35,  p.  1. 

Dale:  Journ.  of  Physiol.,  1906,  vol.  34,  p.  163. 

Fliess:  Die  Bezieh.  zw.  Nase  u.  weibl.  Geschlechtsorgan,  Leipzig  and  Wien,  1897. 

v.  Frankl-Hochwart  u.  A.  Frohlich:  Wiener  klin.  Woch.,  1909,  No.  27. 

1Kehrer,  E.:  Arch.  f.  Gyn.,  vol.  81. 

'Kehrer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  58,  p.  366. 

3Kehrer:    Arch.  f.  Gyn.,  1906,  vol.  81. 

«Kehrer:  Arch.  f.  Gyn.,  1910,  vol.  90,  p.  169. 

Kehrer,  F.:  Beitr.  z.  vergl.  u.  experim.  Geburtskunde,  Giessen. 

Kleinwachter :  Arch.  f.  Gyn.,  1878,  vol.  13,  p.  280. 

1  Kurdinowski :  Engelmann's  Arch.  f.  Physiol.,  Suppl.,  1904,  p.  323. 

2  Kurdinowski :  Arch,  f .  Gyn.,  1906,  vol.  78,  p.  34. 
Langley  and  Anderson:  Journ.  of  Physiol.,  1895,  vol.  19. 
Maurer:  Deut.  med.  Woch.,  1907,  p.  173. 

Rohrig:  Virchow's  Arch.,  1879,  vol.  76,  p.  1. 
Schiff,  A.:  Chrobak's  Festschrift,  1903,  p.  374. 

In  practice,  ergot,  hydrastis,  and  cotarnine,  and  quite  recently 
epinephrin  and  pituitrin,  are  employed  for  the  purpose  of  exciting 
or  strengthening  uterine  contractions. 

ERGOT 

ERGOT  (Secale  cornutum)  is  the  sclerotiuin  of  the  fungus  Claviceps 
purpurea,  which  causes  a  fungous  disease  in  various  grains,  especially 
in  rye  during  wet  seasons. 

In  former  times  ergot  caused  very  severe  epidemics  of  ergotism,  and 
even  in  recent  decades  such  epidemics  have  occurred  in  many  civilized 
countries.  (1867-8  in  East  Prussia,  1894  in  Nanterre,  France,  1907-8 
in  Hungary,  and  in  numerous  years  in  various  districts  in  Russia.) 
When  ergot  is  ground  with  the  grain,  as  much  as  6-10  per  cent,  may 
be  present  in  bread  and  foods  made  from  the  flour,  and  even  i/o-l  per 
cent,  is  enough  to  cause  poisoning.  In  epidemics  two  types  of  disease 
occur,  a  convulsive  and  a  gangrenous  type,  one  type  or  the  other  being 
usually  the  prevailing  one  in  a  given  epidemic,  although  epidemics 
have  been  described  in  which  one  type  alone  was  observed  (Robert 1). 


ERGOT  225 

The  varying  clinical  picture  of  spasmodic  or  convulsive  ergotism  starts  with 
a  feeling  of  numbness  in  the  fingers,  which  spreads  over  the  whole  body;  later 
gastro-intestinal  disturbances,  with  vomiting  and  purging,  develop,  and  still 
later  the  typical  spasms.  These  consist  in  very  painful  tonic  contractions  of  the 
muscles,  occurring  at  intervals  and  affecting  especially  the  flexors  of  the  extremi- 
ties and  leading  to  typical  contractures.  In  addition,  there  may  finally  occur 
clonic  epileptiform  convulsions,  which  may  last  for  hours.  The  contractures 
remain  permanently,  and  with  them  serious  disturbances  of  the  nervous  system, 
such  as  pseudo-tabes  or  imbecility. 

Gangrenous  ergotism  also  often  starts  in  the  same  way,  with  prickling 
and  numbness  of  the  fingers,  vomiting  and  diarrhoea,  and  after  some  days  the 
typical  lesions  of  gangrene.  In  these  the  skin  over  the  affected  parts  loses  its 
natural  color  and  turns  black  and  blue,  the  epidermis  is  raised  up  over  the 
gangrenous  spots,  and  dry  gangrene  of  whole  toes  and  fingers  may  result,  and  at 
times  also  of  the  ears  or  nose.  The  development  and  limitation  of  the  gangrene 
is  at  first  accompanied  by  very  severe  pain,  but  later  complete  anaesthesia  develops. 

During  such  epidemics  abortions  and  miscarriages  are  often  observed,  and 
consequently  as  early  as  the  17th  century  ergot  was  employed  as  an  oxytocic. 
On  account  of  its  abuse,  the  drug  soon  fell  into  disrepute,  and  its  use  was  much 
opposed  and  was  even  forbidden  at  the  end  of  the  18th  century,  but  early  in 
the  19th  century  it  was  re-introduced  into  therapeutics, 

Practical  experience  obtained  from  the  use  of  ergot  indicates  a 
threefold  action  of  the  drug, — the  first  that  of  exciting  spasms,  which 
is  responsible  for  the  convulsive  ergotism;  the  second  that  of  causing 
gangrene,  which  is  responsible  for  the  gangrenous  ergotism;  and  the 
third  and  most  important,  its  action  on  the  uterus.  In  addition,  active 
preparations  of  ergot  cause  vasoconstriction  and  a  rise  in  'blood- 
pressure.  In  spite  of  many  laborious  investigations,  for  a  long  time 
little  advance  was  made  in  determining  which  constituents  of  ergot 
were  responsible  for  these  different  actions,  but  recent  efforts  have 
been  more  successful. 

ACTIVE  PRINCIPLES. — Extracts  of  ergot  are  mixtures  of  complicated 
and  inconstant  composition,  from  which  there  have  been  prepared 
at  least  three  pure  substances,  which  are  concerned  in  its  pharmaco- 
logical actions.  One  of  these,  ergotoxin  (Kraft,  Barger,  Carr  and 
Dale1,2,3),  an  amorphous  alkaloid,  exerts  the  specific  characteristic 
action  of  ergot.  In  addition  to  it,  ergot  extracts  contain  at  least  two 
physiologically  very  active  ptomaine-like  bases,  which  are  formed 
either  by  the  metabolism  of  the  fungus  or  by  the  actions  of  micro- 
organisms on  organic  mother  substances  (Barger  and  Dale  1»3). 

Inactive  Constituents. — Besides  these  three  active  ingredients,  ergot  contains 
a  large  number  of  less  active  substances, — for  example,  leucine  ( Buchheim,  Barger 
and  Dale),  uracil,  tetra-  and  pentamethylenediamine,  betaine,  and  choline 
(Rielander) .  As  a  means  of  recognizing  the  presence  of  ergot  in  bread  and 
flour,  considerable  interest  attaches  to  sclererythrin,  a  red  coloring  matter  of 
acid  character,  which,  along  with  other  coloring  matters,  occurs  in  the  drug 
combined  with  Ca  and  Mg.  It  passes  readily  from  acidified  water  into  ether 
and  may  be  readily  identified  chemically  and  spectroscopically. 

ERGOTOXIN. — According  to  a  number  of  investigators  (Kraft,  Bar- 
er, Carr  and  Dale  1>2>3),  there  is  present  in  ergot  a  crystalline  alkaloid, 
•otinin,  first  prepared  by  Tanret.   This  has  no  action  on  the  uterus, 
t  is  accompanied  by  its  amorphous  hydrate;  hydro-ergotinin   or 

15 


226       PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

ergotoxin,  which  apparently  is  the  most  important  constituent  of  the 
drug.  According  to  Dale,  when  administered  subcutaneously  or  intra- 
venously this  substance  causes  contraction  of  unstriped  muscle,  espe- 
cially of  the  uterine  muscle,  a  rise  in  blood-pressure  due  to  vasocon- 
striction,  and  also  the  characteristic  ergot  gangrene.  The  rise  in 
blood-pressure  is  due  to  peripheral  action  and  is  very  persisting, 
but  after  large  doses  this  primary  excitation  of  the  vasoconstrictor 
nerve-endings  is  followed  by  an  elective  depression  of  the  pressor 
sympathetic  nerves,  so  that  the  blood-pressure  falls  and  can  no  longer 
be  raised  by  epinephrin,  but  under  these  conditions  is  actually  lowered 
by  it  (Dale's  vasomotor  paradox). 

Aqueous  extracts  of  ergot  also  contain  two  very  active  bases,  which 
in  their  actions  closely  resemble  epinephrin,  parahydroxyphenylethyla- 
mine  (Barger  and  Dale1'-),  formed  from  tyrosine  in  the  mycelium 
of  the  fungus  by  bacterial  action,  which  is  a  very  powerful  vasocon- 
strictor, and  (3-imidazolylethylamine  (Barger  and  Dale3),  similarly 
formed  from  histidine,  which  even  in  enormous  dilutions  excites  violent 
uterine  contractions. 

Other  Alkaloids. — Formerly  the  specific  actions  of  ergot  were  attributed 
to  various  alkaloids  (Robert2)  and  resinous  substances  combined  with  them 
(Jacobi). 

Among  these  alkaloids  the  substance  known  as  cornutine  for  a  time 
attracted  considerable  attention,  but  later  investigations  have  shown  it  to  be, 
not  a  pure  substance,  but  a  mixture  of  various  alkaloids,  among  which  ia 
ergotoxin,  and  that  it  has  little  or  no  therapeutic  activity.  It  is,  however, 
possible  that  this  mixture  of  alkaloids  known  as  cornutine,  and  perhaps  their 
decomposition  products,  which  are  present  in  ergot,  are  responsible  for  the 
convulsive  actions  of  ergot,  for  it  causes  typical  tonic  and  clonic  convulsion* 
and  behaves  like  a  typical  convulsant.  As,  however,  it  is  not  always  a  con- 
stituent of  ergot  and  as  no  one  has  yet  succeeded  in  producing  chronic  poisoning 
in  animals  by  its  administration,  its  significance  for  convulsive  ergotism  is  still 
uncertain  (tichmiedeberg).  Cornutine  excites  uterine  contractions  by  an  action 
on  the  central  nervous  system,  but  some  observers  have  found  it  effective  in 
surviving  uterus,  which  may  be  explained  by  its  containing  ergotoxin. 

Resinous  substances  which  are  present  in  ergot,  combined  with  inert  alka- 
loidal  substances,  have  also  been  considered  as  the  constituents  responsible  for 
the  specific  effects  of  the  drug.  Among  such  are  sphacelic  acid  (Robert3) 
and  sphacelotoxin,  which  latter,  although  possessing  no  true  acid  properties, 
readily  combines  with  other  substances,  forming,  among  other  compounds, 
chrysotoxin  and  secalintoxin  (Jacobi).  According  to  more  recent  investigators 
(Kraft,  Barger  and  Dale*),  these  are  not  chemical  entities,  Dale  claiming  that 
the  nitrogenous  component  of  the  mixture  is  identical  with  ergotoxin.  Robert  * 
and  Jacobi,  from  their  observations  on  animals,  believed  that  the  poisonous 
resinous  acids  and  their  salts  were  the  substance  which  caused  the  gangrene, 
but  recently  Rraft  and  Barger  and  Dale  have  attributed  this  effect  to  ergotoxin. 

Experimentally  the  gangrene  is  best  produced  in  the  cock's  comb  and  in 
the  pig's  snout.  It  is  due  to  a  peculiar  change  occurring  in  the  vessel  walls, 
a  hyaline  thrombosis  of  the  smallest  arteries,  which  develops  in  the  periphery 
as  a  result  of  the  stasis  resulting  from  the  toxic  contraction  of  the  vessels. 

From  this  short  survey  of  the  more  important  points  bearing  on  the 
chemistry  of  ergot  and  its  constituents,  it  is  evident  that  much  uncer- 
tainty still  obtains  as  to  the  chemical  properties  and  the  homogeneity 
of  the  various  substances  prepared  from  it,  and  also  as  to  their 


ERGOT  227 

activity.  In  view  of  these  contradictions  especially,  little  may  be 
maintained  with  certainty  as  to  the  chemical  composition  of  the  con- 
stituents which  cause  the  specific  effects  on  the  uterus. 

There  is  no  doubt,  however,  that  this  substance — or  these  substances 
— are  readily  extracted  -by  water  and  less  readily  by  alcohol.  The  fact 
that  such  difficulties  have  attended  the  efforts  made  to  isolate  the 
substance  acting  on  the  uterus,  and  that  repeatedly  new  substances 
have  been  described  as  the  true  active  principle,  is  due  both  to  the 
marked  instability  of  the  active  substances  and  to  the  very  active  reac- 
tion of  the  uterus,  especially  when  gravid,  to  various  toxic  substances, 
central  excitants  acting  on  the  uterus  through  the  centres  while  the 
sympathetic  and  autonomic  poisons  act  on  the  nerve-endings  in  the 
uterus  itself.  In  addition,  the  interpretation  of  experimental  results 
is  rendered  still  more  difficult  by  the  fact  that  the  uterus  may  be 
affected  by  various  reflexes  and  by  such  factors  as  asphyxia,  in  such 
fashion  that  it  may  appear  that  it  is  directly  affected  by  a  drug 
when  this  is  not  the  case. 

Instability  of  the  Active  Principles. — As  the  substances  acting  on 
the  uterus  so  readily  undergo  change,  the  apothecary  should  renew 
his  supply  each  year.  [This  is  legally  obligatory  in  Germany. — TR.] 
Ergot  is  most  active  before  the  rye  has  ripened.  When  stored  its 
specific  (uterine)  activity  gradually  diminishes,  until  at  the  end  of  a 
year  it  possesses  only  one-seventh  to  one-eighth  of  its  original  activity, 
and  at  the  end  of  two  years  only  one-fifteenth  (E.  Kehrer).  The 
substance  causing  gangrene  appears  to  be  even  more  unstable,  for  the 
effect  on  the  cock's  comb,  according  to  Robert  and  Griinfeld,  can  be 
obtained  only  in  the  first  few  months  following  the  harvest,  being 
markedly  weaker  in  November  and  having  entirely  disappeared  by  the 
following  March. 

PHYSIOLOGICAL  ASSAY. — This  effect  on  the  cock's  comb  (Kehrer), 
the  action  on  the  blood-pressure  (Dale,  Wood  and  Hofer),  and  the 
excitation  of  the  surviving  cat's  uterus  (Kehrer),  have  all  been 
employed  as  methods  of  physiological  assay.  As  these  different  effects 
are  in  part  due  to  different  constituents,  it  is  evident  that  the  results 
of  the  assay  will  vary  with  the  method  employed  (Crony n  and  Hender- 
>i).  As  ergot  is  chiefly  employed  for  its  effects  on  the  uterus,  the 

<st  rational  assay  method  is  that  in  which  the  cat's  uterus  is 
employed. 

It  can  be  demonstrated  that  ergot  extracts  excite  contractions  in 
the  uterus  surviving  in  Ringer's  solution,  increased  tone  and  strength- 
ening of  the  autonomic  contractions  resulting  from  ordinary  doses, 
and  tonic  contractions  from  larger  ones.  This  action  is,  therefore,  a 
peripheral  one,  agreeing  qualitatively  with  the  effect  of  intravenous 
jection  of  active  extracts  on  uterine  movements  in  the  living  animal. 
rgotoxin  and  (3-imidazolylethylamine  are  the  only  two  substances 


228       PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

which  have  thus  far  been  prepared  in  pure  form  and  which  produce 
this  characteristic  action. 

VASOCONSTRICTOR  ACTION. — Certain  of  the  active  principles  of  ergot 
also  act  on  the  vessel  walls  or  on  the  vasomotor  nerve-endings  in  them, 
and,  therefore,  active  ergot  extracts  may  raise  the  blood-pressure. 
This  action  is  also  a  peripheral  one,  and  appears  to  be  due  to  ergo- 
toxin  and  hydroxyphenylethylamine. 

THERAPEUTIC  EMPLOYMENT. — In  obstetrical  practice  ergot  is  no 
longer  used  to  strengthen  uterine  contractions  during  labor,  for  the 
inconstant  strength  of  its  preparations  renders  the  dosage  uncertain, 
and,  therefore,  there  is  danger  of  causing  tonic  contraction  of  the 
uterus  and  death  of  the  child;  but,  after  delivery  of  the  child  and 
loosening  of  the  placenta,  it  is  generally  used  for  the  purpose  of 
checking  hemorrhage  and  to  bring  about  a  firm  and  lasting  contraction 
of  the  uterus.  The  effects  in  checking  hemorrhage  under  such  con- 
ditions have  been  attributed  to  a  contraction  of  the  uterine  vessels 
under  the  influence  of  the  drug,  but  this  is  not  strictly  the  case. 
However,  the  contraction  of  the  uterine  muscle,  which  is  excited  by 
ergot,  itself  acts  to  check  bleeding,  for  the  uterine  vessels  are  enclosed 
in  a  mesh  of  uterine  muscles,  and  when  the  muscles  contract  they 
are  compressed  so  that  the  formation  of  thrombi  is  favored.  This  is 
the  reason  why  ergot  is  so  efficient  in  checking  uterine  hemorrhage, 
although  its  action  on  other  hemorrhages  is  so  uncertain.  The  stop- 
page of  uterine  hemorrhage  could  be  attributed  to  a  direct  action  on 
the  vessels  only  on  the  hypothesis  that  only  the  uterine  vessels  ai 
constricted  and  that  no  extensive  vasoconstriction  occurs  elsewhere, 
for  otherwise  a  general  rise  in  blood-pressure  would  result  and  the 
checking  of  the  hemorrhage  would  actually  be  rendered  more  difficult. 

PREPARATIONS. — In  addition  to  powdered  ergot,  numerous  other 
officinal  and  non-officinal  preparations  are  employed.  [In  this  coun- 
try the  fluidextracts  are  almost  exclusively  employed.  For  practice 
purposes  an  aseptic,  physiologically  assayed  fluidextract  is  to  be  pre 
ferred,  but  such  preparations  also  become  inert  quickly,  and  theref 01 
an  effort  should  always  be  made  to  secure  a  fairly  fresh  preparation.- 
TR.]  It  is  to  be  hoped  that  before  long  these  preparations  of  incon- 
stant composition  and  uncertain  strength  will  be  superseded  by  the 
therapeutically  valuable  substances  in  pure  and  stable  form.  Until 
this  is  attained  it  is  desirable  that  a  satisfactory  method  of  physio- 
logical assay  should  be  devised  and  worked  out  thoroughly  (Gottlieb). 

BIBLIOGRAPHY 

1Barger  and  Dale:  Journ.  of  Physiol.,  1909,  vol.  38. 
'Barger  and  Dale:  Transact.  Chem.  Soc.,  1909,  vol.  95. 
8  Barger  and  Dale:  Journ.  of  Physiol.,  1910,  vol.  40. 
Barger  and  Dale:  Arch.  d.  Pharmazie,  1906,  vol.  244. 

1  Barger,  Carr  and  Dale:  Chem.  News,  1906,  vol.  94,  p.  89. 

2  Barger,  Carr  and  Dale:  Journ.  Chem.  Soc.,  1907,  vol.  91,  p.  337. 
*  Barger,  Carr  and  Dale:  Biochem.  Journ.,  1907,  vol.  2,  p.  240. 


HYDRASTIS  AND  COTARNINE  229 

Bennecke:  Arch.  f.  Gyn.,  1908,  vol.  83,  p.  669. 

Buchheim:   Arch.  f.  Pharm.,  1875.,  vol.  2. 

Cronyn  and  Henderson:  Journ.  of  Pharm.  and  exp.  Ther.,  1909,  vol.  1,  p.  203. 

Dale:  Journ.  of  Physiol.,  1906,  vol.  34,  p.  163. 

Gottlieb:  Miinchn.  med.  Woch.,  1908,  p.  1265. 

Jacob! :  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  84. 

Kehrer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  58. 

1Kobert:  Historische  Studien  a.  d.  Pharm.  Inst.  zu  Dorpat,  1891. 

'Robert:   Realencyclopadie  d.  gesamt.  Pharmazie,  1889,  Mutterkorn. 

•Kobert:  Arch.  f.  exp.  Path.  u.  Pharm.,  1884,  vol.  18,  p.  316. 

Kobert  u.  Griinfeld:  Arb.  d.  Pharm.  Inst.  zu  Dorpat,  1892,  vol.  8,  p.  109. 

Kraft:  Arch.  f.  Pharm.,  1906,  vol.  244,  p.  336. 

Rielander:  Marburger  Sitzungsber.,  1908,  p.  173. 

Schmiedeberg :  Grundriss  d.  Pharmakol.,  5th  Ed.,  p.  296. 

Vahlen:    Arch.  f.  exp.  Path.  u.  Pharm.,  1906,  vol.  55. 

Vahlen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 

Wood  and  Hofer:  Arch,  of  Int.  Med.,  1910,  vol.  6,  p.  388. 

PREPARATIONS  OF  HYDRASTIS  AND  OF  COTARNINE  are  also  employed  in 
uterine  hemorrhage.  Hydrastine,  from  Hydrastis  canadensis,  and  its 
derivative  hydrastinine,  also  possess  a  peripheral  exciting  action  on  the 
uterus  (E.  Kehrer).  Both  alkaloids,  but  more  especially  hydrastinine, 
cause  a  general  vasoconstriction  and  a  rise  of  the  blood-pressure,  due 
both  to  a  stimulation  of  the  vasomotor  centres  and  to  a  peripheral 
vasoconstricting  action  (Falk,  Marfori).  An  entirely  similar  effect 
on  the  uterus  is  produced  by  cotarnine,  which  is  a  methyloxyhydras- 
tinine  prepared  from  narcotine,  an  inactive  opium  alkaloid  (Freund). 
This  drug,  like  the  others,  also  acts  on  the  uterus  directly.  Its  hydro- 
chloride  and  its  phthalate  are  obtainable  under  the  trade  names  of 
stypticin  and  styptol,  and  are  employed  in  the  treatment  of  uterine 
hemorrhage  and  also  as  uterine  sedatives  in  disturbances  of  the  men- 
strual function. 

Quite  recently  epinephrin  has  been  employed  for  its  effects  on  the 
uterus  (Neu).  Its  energetic  oxytocic  action  has  already  been  men- 
tioned. On  account  of  the  readiness  with  which  it  undergoes  change 
in  the  organism,  neither  its  intrauterine  nor  hypodermic  administra- 
tion causes  much  rise  of  blood-pressure,  but  the  small  amounts  which 
remain  unchanged  are  sufficient,  even  after  hypodermic  administra- 
tion, to  excite  or  to  strengthen  the  contractions  of  the  very  readily 
excited  muscle-fibres  of  the  gravid  uterus.  It  may,  therefore,  be  used 
subcutaneously  for  the  induction  of  labor,  to  strengthen  labor  pains, 
or  to  check  uterine  hemorrhage. 

After  the  birth  of  the  child  the  use  of  this  drug  is  free  from 
danger,  but  clinical  experience  must  decide  whether,  with  careful 
dosage,  its  use  during  labor  is  unattended  with  risk  of  causing  tonic 
contraction  of  the  uterus  with  its  peril  to  the  child. 

This  drug  has  also  been  directly  injected  into  the  uterine  muscle 
to  check  post-partum  hemorrhage,  and  also  during  caesarian  section, 
both  to  render  the  uterus  bloodless  for  a  time,  and  to  secure  its 
aximal  contraction. 


230      PHARMACOLOGY  OF  REPRODUCTIVE  ORGANS 

According  to  still  more  recent  observations,  extracts  of  the  infun- 
dibular portion  of  the  hypophysis  act  like  "a  mild  and  under  all 
conditions  harmless  epinephrin,"  which  may  be  used  in  the  same 
indications  (Foges  and  Hofstattcr,  Hofbauer,  Neu). 

BIBLIOGRAPHY 

Falk:  Therap.  Monatsh.,  1896,  p.  28. 

Foges  u.  Hofstatter:  Zentralbl.  f.  Gyn.,  1910,  No.  46. 

Freund:  Therap.  Monatsh.,  1904,  p.  413. 

Hofbauer:  Zentralbl.  f.  Gyn.,  1911,  No.  4. 

Kehrer,  E.:    Monatsschr.  f.  Geb.  u.  Gyn.,  1907,  vol.  26,  p.  709. 

Marfori:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  161. 

Neu:  Gynakologische  Rundschau,  1907,  p.  507. 

Neu:  Die  Bedeut.  d.  Suprarenins  f.  d.  Geburtshilfe,  Berlin,  1908. 

Neu:  Miinchn.  med.  Woch.,  1911,  No.  11. 


CHAPTER  VIII 


FACTORS   CONTROLLING   THE   CIRCULATION 

BLOOD  flow  and  blood-pressure  are  governed  by  three  factors, — the 
quantity  and  quality  (viscosity)  of  the  blood,  the  work  done  by  the 
heart,  and  the  calibre  of  the  vessels  and  their  activity.  The  rapidity 
of  the  flow  through  the  whole  circulation  depends  on  the  reciprocal 
relationship  of  these  factors.  Directing  our  attention  to  the  separate 
vascular  systems,  we  may  for  the  time  being  consider  the  work  done 
by  the  heart  and  the  volume  of  the  blood  as  constant,  while  the  third 
factor — that  is,  the  state  of  contraction  of  the  vessels — changes  from 
moment  to  moment  according  to  the  needs  of  the  various  organs. 

In  general  it  may  be  said  that,  under  physiological  conditions,  the 
more  active  an  organ  is  the  more  blood  will  it  contain,  for,  as  every- 
where in  the  body,  the  rule,  that  a  physiological  activity  brings  about 
conditions  which  favor  its  efficient  accomplishment,  holds  good  for  the 
relationship  between  the  activity  of  an  organ  and  its  blood  supply. 
The  demand  creates  a  supply,  so  that  the  activity  of  an  organ  governs 
its  blood  supply. 

This  vasodilatation  of  active  organs  is  brought  about  by  reflexes  causing 
inhibition  of  vasoconstriction  as  well  as  stimulation  of  vasodilators,  and  sub- 
stances formed  during  the  activity  of  the  organ  act  locally  on  the  vessel  walls, 
causing  local  vasodilatation  ( Gaskell,  Loeioi  u.  Henderson) . 

The  activity,  or  inactivity,  of  the  various  organs  may  bring  about 
very  marked  changes  in  the  distribution  of  the  blood.  The  muscles  of 
a  rabbit  at  rest  contain  but  33.6  per  cent,  of  the  total  blood,  but 
this  percentage  is  increased  to  66  per  cent,  or  more  during  violent 
muscular  effort  (Ranke  u.  Spehl).  With  the  dilatation  of  so  many 
vessels  resulting  from  general  muscular  activity  and  the  resultant 
decrease  of  the  resistance,  there  would  necessarily  be  a  very  marked 
fall  in  the  general  blood-pressure,  and  a  slackening  of  the  blood  flow 
in  other  organs  (e.g.,  in  the  heart  and  central  nervous  system),  were 
there  not  an  efficient  compensating  mechanism  to  prevent  this.  The 
conditions  which  prevail  during  muscular  activity  show  that  there 
is  ample  provision  for  such  compensation,  for,  as  a  matter  of  fact, 
blood-pressure  actually  rises  during  muscular  activity  (Zuntz  u. 
Tangl,  Tiedcmann,  Krone}.  This  compensation  is  brought  about 
not  only  by  an  increased  efficiency  of  the  heart  function,  but  also 
by  a  narrowing  of  the  vessels  in  other  organs, — e.g.,  the  portal  vessels, 
—which  compensates  for  the  dilatation  of  the  vessels  in  the  muscles. 
On  the  other  hand,  although  during  digestion  the  abdominal  viscera 
are  more  richly  supplied  with  blood,  the  other  organs  receive  com- 

231 


232  PHARMACOLOGY  OF  CIRCULATION 

paratively  little,  so  that  the  aortic  pressure  is  not  necessarily  lowered 
(Pawlow). 

There  is  thus  a  continuous  compensatory  balance  maintained  be- 
tween the  different  vascular  systems,  especially  between  the  portal 
system  and  the  peripheral  vessels  in  the  skin,  muscles,  and  brain.  This 
reciprocation  between  these  two  great  systems  is  well  illustrated  when 
the  depressor  nerve  is  stimulated,  there  resulting  a  dilatation  of  the 
visceral  vessels  and  a  contraction  of  the  peripheral  ones  (Bayliss, 
Dastre  et  Moral}.  On  the  other  hand,  stimulation  of  sensory  nerves 
or  of  the  splanchnics,  or  asphyxia,  causes  a  vasoconstriction  of  the 
abdominal  vessels  and  dilatation  of  most  of  the  vessels  of  the  skin, 
muscles,  and  brain.  We  find  this  same  difference  in  behavior  resulting 
from  the  administration  of  various  drugs  (epinephrin,  digitalis,  strych- 
nine, and  others) .  Other  combinations  are  also  possible, — for  example, 
cold  applied  to  the  skin  causes  contraction  of  the  cutaneous  and  renal 
vessels,  while  the  other  visceral  vessels  dilate  ( Wertheimer,  0.  Mutter)'. 
Mental  activity  causes  an  increased  blood  supply  to  the  brain  and  a 
lessened  supply  to  the  skin  and  muscles  of  the  head  and  to  the 
abdominal  viscera  (Mosso,  Weber}. 

This  regulation  of  the  distribution  of  the  blood  is,  in  part,  reflex  in  its 
mechanism.  For  instance,  when  the  internal  vessels  are  constricted,  the  vaso- 
dilatation  in  the  extremities  is  partly  the  result  of  central  nervous  action 
(Delezenne) ,  but  it  also  results  in  part  from  a  forcing  out  of  the  blood  from  the 
constricted  vascular  systems  into  others,  the  vessels  of  which  are  thus  mechani- 
cally dilated.  In  certain  vascular  systems  which  are  little,  if  at  all,  under  vaso- 
motor  control,  the  changes  in  the  blood  supply  are  brought  about  entirely  in 
the  latter  fashion. 

Although  we  have  but  a  limited  knowledge  of  the  details  of  the 
various  compensatory  regulations  by  which  the  different  vascular  sys- 
tems maintain  the  equilibrium  of  the  circulation,  we  know  that  dis- 
turbances of  this  compensatory  mechanism  play  an  important  role  in 
pathology.  We  know  too  that  in  the  circulatory  action  of  drugs  the 
decisive  factor  is  often  the  changed  distribution  of  the  blood  and 
not  the  change  in  the  aortic  pressure.  If,  for  any  reason,  in  con- 
ditions in  which  the  blood  distribution  is  altered  from  the  normal,  this 
compensatory  regulation  does  not  occur,  its  mechanical  results  affect 
the  whole  circulation,  including  the  heart  itself. 

This  occurs  when  important  and  extensive  vascular  systems  are 
relaxed  and  when  compensation  therefor  does  not  occur.  In  such  case 
the  total  amount  of  blood  in  the  body  is  not  sufficient  to  fill  the  relaxed 
vessels,  for  the  total  volume  of  blood  is  sufficient  for  the  filling  of  the 
vascular  systems  only  when  the  total  cross-section  of  the  vascular  tree 
is  equal  to  its  normal  mean,  which  mean  is  ordinarily  maintained 
by  the  changing  play  of  the  vasomotor  mechanism.  Therefore,  in 
conditions  of  vascular  paresis,  it  is  evident  that  the  heart  is  unable 
to  work  efficiently,  for,  when  the  vascular  system  has  lost  its  tone,  the 
left  heart  pumps  its  blood  not  into  an  elastic  system  of  tubes  which 


FACTORS  CONTROLLING  CIRCULATION  233 

are  able  to  deliver  their  contents  back  to  the  right  heart,  but  it  pours 
it  out  into  a  relaxed  system  in  which  the  blood  must  stagnate  to  a 
greater  or  less  extent.  As  a  result  the  heart  is  insufficiently  supplied 
with  blood. 

As  shown  above,  uncompensated  vasodilatation  impairs  the  heart 
action,  and  the  same  is  true  when  wide-spread  vasoconstriction  occurs. 
In  the  latter  case,  as  a  result  of  the  increased  peripheral  resistance,  the 
blood-pressure  must  rise  greatly,  and,  if  compensatory  relaxation  of 
other  vessels  does  not  occur  to  relieve  the  heart,  the  left  ventricle  may 
no  longer  be  able  to  empty  itself  against  the  excessive  pressure,  and 
stasis  of  the  blood  in  the  heart  results  (Tig erst edt) . 

This  short  discussion  has  already  shown  how  the  activity  and 
efficiency  of  the  heart  depend  on  the  maintenance  of  a  mean  total 
cross-section  of  the  vascular  tree  by  the  interplay  of  the  different 
vascular  systems  (Henseri).  Clinically,  this  is  clearly  evident,  for, 
under  different  conditions  of  increased  or  diminished  cardiac  activity 
(tachycardia,  fever,  disturbance  of  compensation,  etc.),  causing  marked 
variations  in  the  blood  flow,  there  may  be  no  change  in  the  radial 
blood-pressure,  the  vascular  system  by  compensatory  dilatation  or 
contraction  accommodating  itself  to  the  varying  output  of  the  heart. 
Ever  since  the  observations  of  Tappeiner  and  Worm-Mutter,  it  has 
been  known  that  the  blood-pressure  quickly  regains  its  former  height 
even  after  extensive  loss  of  blood,  and  it  is  under  just  these  conditions 
that  we  may  especially  well  observe  this  accommodation  of  the  vascular 
system  to  varying  states  of  fulness.  Although  after  hemorrhage  an 
inpouring  of  fluid  from  the  lymph  and  tissues  plays  an  important  part 
m  restoring  the  blood-pressure,  its  rapid  re-establishment  is  chiefly 
due  to  the  fact  that  the  vessels  throughout  the  body  contract  about 
their  diminished  blood  contents.  On  the  other  hand,  in  artificial 
plethora  the  blood-pressure  is  raised  only  by  very  great  overfilling 
of  the  vascular  system,  and  even  then  but  momentarily  ( Cohriheim) . 

The  circulation  is  further  protected  from  disturbance  by  another 
adaptive  mechanism,  which  helps  to  maintain  the  proper  equilibrium 
between  the  arterial  and  venous  systems.  If  the  blood  Is  to  be  kept 
circulating  normally,  it  is  essential  that  during  a  given  period  the  same 
quantity  of  blood  must  pass  each  total  cross-section  of  the  vascular 
tree, — that  is,  in  a  given  period  as  much  blood  must  enter  the  heart 
from  the  veins  as  leaves  it  to  enter  the  arteries.  If  this  balance  be 
disturbed,  the  blood  will  accumulate  in  some  portion  of  the  circu- 
latory system,  most  likely  either  in  the  heart  itself  or  at  the  point 
where  the  arterioles  and  capillaries  join  with  the  veins.  Epinephrin 
injections,  by  increasing  the  resistance  in  the  arterioles,  may  cause  an 
overfilling  of  the  arterial  portion,  or  a  dilatation  of  the  capillaries 
may  cause  an  accumulation  at  this  point  with  a  resulting  "capillary 

is, ' '  while  insufficient  cardiac  activity  may  lead  to  an  accumulation 


234  PHARMACOLOGY  OF  CIRCULATION 

of  blood  in  the  heart  itself,  in  the  pulmonary  system,  and  in  the 
great  veins  emptying  into  the  heart, — "cardiac  stasis." 

Everywhere  we  see  that  disturbances  of  the  heart  function  produce 
effects  on  the  vascular  system  and  that  the  changes  in  the  vessels 
affect  the  cardiac  function.  With  such  reciprocal  action  of  the 
separate  factors  and  such  mutual  interdependence,  it  is  evident  that 
there  can  be  no  such  thing  as  a  pharmacological  action  affecting  exclu- 
sively either  the  heart  or  the  vessels,  for,  just  as  pathological  altera- 
tions of  the  heart  or  vessels  necessarily  affect  the  whole  circulation,  so 
it  is  with  those  produced  by  pharmacological  agents.  Bearing  these 
facts  in  mind,  it  is  evident  that,  in  the  analysis  of  pharmacological 
actions  of  the  various  circulatory  drugs,  it  is  essential  to  determine 
their  primary  seat  of  action,  as  this  often  renders  it  possible  to  explain 
the  whole  combination  of  the  phenomena  resulting  from  their  adminis- 
tration. Therefore  the  action  of  drugs  on  the  heart  and  on  the  vessels 
will  be  discussed  separately,  while  their  effects  on  the  circulation  as  a 
whole  will  be  taken  up  later.  Moreover,  in  any  investigation  of  such 
drugs  one  should  first  of  all  endeavor  to  determine  whether  a  drug  acts 
primarily  on  the  heart  or  on  the  vessels. 

BIBLIOGRAPHY 

Bayliss:    Journ.  of  Physiol.,  1893,  vol.  14,  p.  303. 

Cohnheim:    Vorles.  u.  allgem.  Pathologie,  1882,  vol.  1,  2d  ed.,  p.  400. 

Dastre  et  Morat:   Systeme  nerveux  vasomoteur,  Paris,  1884,  p.  330. 

Delezenne:  Journ.  of  Physiol.,  23,  Suppl.,  1898-1899,  p.  4. 

Gaskell:  Journ.  of  Physiol.,  1880-1882,  vol.  3,  p.  48. 

Henderson  u.  Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  53,  p.  62. 

Hensen:   Deut.  Arch.  f.  klin.  Med.,  1900,  vol.  47. 

Krone:    Miinchn.  med.  Woch.,  1908,  No.  2. 

Mosso:  Arch.  ital.  de  Biol.,  1884,  vol.  5. 

Miiller:   Deut.  Arch.  f.  klin.  Med.,  1905,  vol.  82,  p.  574. 

Pawlow:  Pfliiger's  Arch.,  1879,  vol.  20,  p.  210. 

Ranke  u.  Spehl:    cited  from  Tigerstedt,  Physiol.  d.  Kreislaufes,  1893,  p.  551. 

Tiedemann:  Deut.  Arch.  f.  klin.  Med.,  vol.  91,  p.  331. 

Tigerstedt:   Skand.  Arch.  f.  Physiol.,  1907,  vols.  19  and  20. 

Weber:   Engelmann's  Arch.,  1907,  p.  293,  and  1908,  p.  189. 

Wertheimer:  Arch,  de  Physiol.,  1894,  p.  308. 

Worm-Mliller:  Ludwig's  Arbeiten  aus  d.  Physiol.  Anstalt  in  Leipzig,   1872  and 

1873. 
Zuntz  u.  Tangl:   Pfluger's  Arch.,  1898,  vol.  70,  p.  544. 

METHODS  OF  INVESTIGATING  THE  CIRCULATION 

The  experimental  pharmacology  of  the  circulation  started  with  the 
study  of  the  changes  in  the  aortic  blood-pressure  resulting  from  the 
administration  of  various  drugs  and  poisons.  The  mean  pressure 
in  the  aorta  must  furnish  enough  hydrostatic  pressure  to  maintain 
a  flow  of  blood  through  the  various  organs  which  will  be  sufficient 
properly  to  maintain  their  various  functions.  A  decided  fall  in 
aortic  pressure  is,  therefore,  in  itself  a  sign  of  marked  disturbance 
throughout  the  circulation.  As,  however,  the  aortic  pressure  represents 
only  a  gross  value  resulting  from  the  momentary  efficiency  of  the 


METHODS  OF  INVESTIGATION 


235 


heart  and  the  total  vascular  resistance,  other  supplementary  methods 
are  needed  for  the  determination  of  the  separate  factors. 

Before  starting  on  a  close  analysis  of  the  blood-pressure  as  studied 
in  animal  experimentation,  it  is  proper  to  discuss  briefly  the  methods 
used  in  the  clinical  observations  of  the  circulation  in  man,  for  the 
more  refined  actions  of  drugs  often  stand  out  more  sharply  under 
pathological  than  under  normal  conditions. 

CLINICAL  METHODS 

SPHYGMOGRAMS. — Some  deductions  may  be  made  as  to  the  func- 
tional activity  of  the  heart  and  the  condition  of  the  vessels  from  the 
graphic  registration  of  the  radial  pulse.  The  form  of  the  pulse  wave — 
i.e.,  the  course  of  the  pressure  changes  in  the  radial — is  dependent; 
on  the  one  hand,  on  the  work  done  by  the  heart  and,  on  the  other, 
on  the  resistance  in  the  vascular  system  (0.  Frank).  The  sphygmo- 

FIG.  17a. 


Normal  pulse. 


Dicrotic  pulse — low  peripheral  resistance. 


• 


Tense  pulse — high  peripheral  resistance  (case  of  lead  colic). 

gram  is  altered  from  the  normal  by  various  pathological  conditions, 
as,  for  example,  in  aortic  insufficiency,  by  the  fact  that  the  blood 
leaves  the  arteries  in  both  directions  or  that  in  arteriosclerosis  it 
flows  out  but  slowly  from  the  inelastic  vessels  (Sahli).  In  a  similar 
manner  pharmacological  agents  may  influence  the  form  of  the  pulse- 
wave,  should  they  change  either  the  inflow  into  the  aorta — i.e.,  the 
"pulse  volume"  of  the  heart — or  alter  the  rate  of  outflow  into  the 
capillaries  by  affecting  the  calibre  of  the  vessels.  With  due  allowance 
for  technical  difficulties,  it  may  be  stated,  with  reasonable  certainty, 
that  when  the  peripheral  resistance  is  low  the  dicrotic  wave  will  be 
well  developed  in  the  sphygmogram  while  the  so-called  "elasticity" 
elevations  tend  to  disappear,  while  with  increased  peripheral  resist- 
ance the  opposite  occurs  (Fig.  17a).  In  spite  of  all  uncertainty  in 
the  interpretation  of  sphygmographic  curves,  the  position  of  the 
anacrotic  wave  high  up  on  the  ascending  curve  near  its  summit,  a 
rounded  summit  or  a  plateau-like  one,  indicates  high  tension  in  the 
rteries. 


236  PHARMACOLOGY  OF  CIRCULATION 

Changes  in  the  pulse  tracings  are  frequently  evident  after  the 
administration  of  drugs  and  poisons  which  influence  the  vessel  calibre. 
Thus,  during  the  attacks  of  spasmodic  contraction  of  intestinal  vessels 
which  occur  in  lead  colic,  the  pulse  is  that  of  high  tension,  with  diminu- 
tion or  disappearance  of  the  dicrotic  wave  and  the  presence  of  an 
anacrotic  elevation.  On  the  other  hand,  vasodilating  drugs,  such  as 
chloral  (in  large  doses),  cause  the  pulse  to  resemble  that  of  fever. 
During  the  treatment  of  vascular  spasms  by  amyl  nitrite,  one  may 
often  observe  the  transition  of  the  pulse  from  one  form  to  another 
(Fig.  17b).  In  such  case  the  change  in  the  sphygmogram  is  much 
less  the  result  of  the  vasomotor  changes  in  the  radial  artery  and  its 
branches  than  of  the  alteration  of  the  general  vasomotor  tone,  which 
is  the  decisive  factor  for  the  whole  circulation  (Sahli). 

THE   CLINICAL   DETERMINATION  OP  THE  BLOOD-PRESSURE   is   of  much 

greater  significance  for  the  pathology  and  pharmacology  of  the  circu- 
lation. The  technic  of  blood-pressure  determination  has  in  recent  time 
reached  such  perfection  that  the  maximal  systolic  pressure  may  be 


(6) 


FIG.  17b. — Sphygmograms  from  case  of  lead  colic :  a,  before,  b,  after  inhalation  of  amyl  nitrite. 

determined  with  a  high  degree  of  accuracy,  while  the  diastolic  mini- 
mum may  be  approximately  estimated.*  From  these  two  values  one 
may  determine  the  variation  in  pressure  in  the  radial  arteries  (pulse- 
pressure)  and  its  relation  to  the  mean  pressure.  While  the  older 
methods  of  v.  Basch,  Riva-Rocci,  Gartner,  and  others  gave  clinically 
valuable  but  only  approximately  correct  values,  v.  Recklinghausen's 
modification  of  Riva-Rocci 's  method  has  a  percentage  of  error  of  but 
7  to  9  per  cent,  for  the  maximal  pressure,  as  has  been  shown  by  the 
direct  measurement  of  the  brachial  pressure  in  an  arm  just  prior 
to  amputation.  The  determination  of  the  minimal  diastolic  pressure 
is  more  difficult,  and  up  to  the  present  time  is  attended  by  greater 
factors  of  error.  [See  footnote. — TR.] 

The  most  important  results  obtained  by  clinical  observations  of 
blood-pressure  have  been  the  demonstration  that  a  marked  rise  in 
blood-pressure  often  occurs  in  disease,  but  that,  contrary  to  our  for- 
mer views,  a  marked  fall  in  blood-pressure  actually  occurs  much  less 
frequently,  and  is  observed,  as  a  rule,  only  a  short  time  before  com- 

*  [By  the  ausculatory  method  both  may  be  determined  with  quite  sufficient 
accuracy. — TR.] 


METHODS  OF  INVESTIGATION  237 

plete  failure  of  the  circulation.  Even  in  cardiac  decompensation, 
marked  lowering1  of  the  blood-pressure  is  the  exception,  for  the 
pressure  is  maintained  near  the  normal  level  by  compensatory  vaso- 
constriction,  and  thus  the  best  circulation  possible  is  maintained  in 
the  vital  organs.  This  regulation  by  the  vessels  so  complicates  blood- 
pressure  conditions  that  the  essential  question,  whether  the  primary 
seat  of  a  pharmacological  action  be  in  the  heart,  vessels,  or  nervous 
system,  can  never  be  answered  without  further  information  than  that 
obtained  by  the  methods  discussed  above. 

BIBLIOGRAPHY 

Frank,  0. :  Ztschr.  f .  Biol.,  1905,  vol.  46,  p.  441. 

Miiller,  Otfried:  Med.  Klin.,  1908,  Nos.  2-4. 

v.  Recklinghausen :  Arch,  f .  exp.  Path.  u.  Pharm.,  1906,  vol.  55,  p.  376. 

Sahli :  Klinische  Untersuchungsmethoden,  5th  edition,  1908,  p.  19. 

EXPERIMENTAL  METHODS 

Only  by  closer  analysis  of  the  blood-pressure  in  experiments  on 
animals  can  such  information  be  obtained.  Here  methods  may  be 
used  which  are  beyond  criticism  and  which  enable  us  to  determine 
the  causes  of  rise  or  fall  in  blood-pressure,  at  any  rate  for  those 
grosser  changes  which  are  not  compensated  for  by  the  regulatory 
mechanism. 

A  PALL  IN  THE  AORTIC  PRESSURE  may  be  due  to  the  lessened  inflow 
of  blood  resulting  from  a  diminished  output  by  the  heart,  or  it  may 
result  from  a  lessening  of  the  resistance  in  the  vessels.  If  a  fall  in 
pressure  is  caused  by  a  general  vasodilatation,  then  the  blood-pressure 
will  be  re-established  at  its  normal  level  if  the  total  vascular  cross- 
section  be  artificially  diminished.  This  may  be  accomplished  by  clamp- 
ing the  aorta,  which  will  cause  the  blood-pressure  to  return  to  its 
normal  level  if  lessened  resistance  were  the  cause  of  the  fall. 

It  having  in  this  fashion  been  shown  that  the  fall  of  blood-pressure 
was  due  to  vasodilatation,  it  must  further  be  determined  if  the  loss 
of  vessel  tone  is  due  to  an  interference  with  the  central  or  the 
peripheral  vasoconstrictor  mechanism.  Electric  stimulation  of  the 
vasomotor  centre  in  the  cervical  cord  or  of  the  vasomotor  nerves — e.g., 
the  splanchnics — may  then  be  employed  to  test  the  excitability  of  the 
peripheral  mechanism. 

In  case  a  drug  has  caused  a  RISE  OP  BLOOD-PRESSURE  as  a  result 
of  a  wide-spread  vasoconstriction,  it  must  similarly  be  determined 
whether  this  be  due  to  stimulation  of  central  or  of  the  peripheral 
vasoconstrictor  mechanisms.  To  decide  this,  the  cervical  cord  may 
be  cut  and  the  effect  on  blood-pressure  noted.  To  exclude  action  of 
the  secondary  vasomotor  centres  in  the  cord,  this  too  may  be  de- 
stroyed by  pithing.  Centrally  acting  drugs,  such  as  strychnine,  will 
under  these  conditions  no  longer  raise  the  blood-pressure.  If,  however, 
the  drug  still  affects  the  blood-pressure  in  the  aorta,  it  must  act 


238  PHARMACOLOGY  OF  CIRCULATION 

peripherally — that  is,  in  the  vessel  walls  themselves.  Substances  of 
the  digitalis  group,  epinephrin,  and  barium  salts  are  examples  of  drugs 
which  under  the  above  conditions  may  still  cause  a  marked  rise  of 
blood-pressure. 

If  the  RELAXATION  OP  THE  VESSELS  is  caused  by  depression  of  the 
vasomotor  centres,  the  diminution  in  their  excitability  may  be  fol- 
lowed step  by  step  if  different  stimulating  agents  be  used.  These 
centres  first  lose  their  reflexive  excitability  to  stimulation  through  the 
sensory  nerves,  the  blood-pressure  failing  to  rise  after  stimulation  of 
the  sciatic.  Chemical  stimuli  are  the  next  to  lose  their  effect,  and 
therefore  the  blood  of  asphyxia,  normally  a  vasoconstrictor  stimulant, 
may  be  used  as  a  means  of  testing  their  excitability.  Finally,  in  com- 
plete paralysis  of  the  vasomotor  centres,  even  direct  electric  stimulation 
of  the  cervical  cord  is  without  effect. 

If  the  vascular  paresis  be  peripheral,  it  is  self-evident  not  only  that 
the  above-mentioned  stimulants  of  the  vasomotor  centres  will  produce 
no  effect,  but  also  that  stimulation  of  vasomotor  nerves  will  be  ineffec- 
tual. If,  for  example,  one  is  dealing  with  a  peripherally  induced 
paresis  of  the  portal  vessels,  such  as  occurs  in  arsenic  poisoning,  the 
stimulation  of  the  splanchnics  will,  as  the  poisoning  develops,  produce 
constantly  diminishing  effects. 

Through  such  experiments  it  is  possible  to  determine  definitely 
whether  or  not  the  action  in  question  is  dependent  or  not  on  the  central 
nervous  system.  We  cannot,  however,  by  these  methods  determine 
at  all  whether  the  changes  in  the  blood-pressure  result  exclusively  from 
peripherally  caused  changes  in  the  calibre  of  the  vessels,  or  whether 
they  also  in  part  arise  from  changes  in  the  cardiac  function.  This  may 
be  decided  beyond  question  only  by  a  further  analysis,  during  which 
the  action  on  the  heart  and  that  on  the  vessels  may  be  better  differ- 
entiated. 

Repeatedly  attempts  have  been  made  to  exclude  the  central  vasomotor  inner- 
ration  and  the  peripheral  mechanism  by  the  use  of  large  doses  of  depressing  drugs, 
Buch  as  chloral  hydrate  or  amyl  nitrite,  and  then  to  test  the  action  of  blood- 
pressure-raising  (pressor)  substances.  However,  this  method  of  experimentation 
is  not  free  from  sources  of  error,  for  the  second  drug  may  overcome  the  vascular 
paralysis  and  thus  the  deduction  of  a  pure  cardiac  action  be  unjustified. 

METHODS  FOR  STUDYING  THE  EFFECT  OF  DRUGS  ON  THE 
CARDIAC  FUNCTION 

If  an  effect  on  blood-pressure  is  not  the  result  of  changes  in  the 
calibre  of  the  vessels,  it  has  usually  been  concluded  that  it  is  due  to  a 
change  in  the  work  performed  by  the  heart,  and  the  endeavor  has 
been  made  to  supplement  the  analysis  of  the  blood-pressure  by  ex- 
perimentation on  the  isolated  surviving  heart.  In  addition,  by  the 
simultaneous  graphic  registration  of  the  blood-pressure  and  of  the 
functional  activity  of  the  heart  by  plethysmography  of  this  organ 
or  by  similar  methods,  further  data  for  the  estimation  of  the  activity 


METHODS  OF  INVESTIGATION 


239 


of  the  heart  may  be  obtained.  However,  the  real  decisive  factor,  the 
pulse  volume  of  the  heart,  may  be  exactly  determined  in  the  intact 
circulation  only  by  measuring  the  amount  of  blood  which  the  heart 
pumps  out  into  the  aorta.  The  measurement  of  the  volume  per 
minute,  by  the  use  of  a  Tigerstedt's  "  Stromuhr  "  placed  in  the  aorta, 
has  recently  given  results  of  much  importance  in  connection  with  the 
study  of  the  action  of  epinephrin,  the  digitalis  group,  etc. 

BIBLIOGRAPHY 

Knoll:    Bericht  d.  Wien.  Akad.  d.  Wiss.,  1880,  vol.  82. 

Lehndorff:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  61,  p.  418. 

Roy  and  Adams:   Philosoph.  Transact,   vol    183    p.  302. 

Tigerstedt:   Skandinav.  Arch,  f    Physiol.    1891,  vol.  3,  and  1907,  vol.  19. 

Observations  on  the  isolated  frog 's  heart  have  rendered  to  pharma- 
cology invaluable  service  in  the  determination  of  the  seat  of  action  of 
drugs  affecting  the  circulation,  the  classical  material  for  such  observa- 
tions being  the  surviving  frog's  heart. 


FIG.  18. — Williams's  frog-heart  apparatus. 

In  1866  Cyon,  in  C.  Ludwig's  laboratory,  was  the  first  to  conduct  such 
experiments.  Soon  after  this  W.  Blasius  and  Bohm  used  the  same  method  in 
Pick's  laboratory.  At  first  the  frog's  heart  was  used  with  the  sinus,  auricles, 
and  valves  attached,  the  heart  receiving  the  artificial  nutrient  solution  (diluted 
blood,  rabbit  serum,  or  Ringer's  solution)  through  one  vena  cava  and  expelling 
it  through  the  aorta,  the  other  veins  and  arteries  having  been  ligated.  The 
observation  of  the  surviving  frog's  ventricle  was  further  simplified  by  the  use 
of  Kronecker's  frog-heart  manometer,  in  the  use  of  which  a  double  cannula  was 
introduced  into  the  ventricle  after  removal  of  both  sinus  and  auricle.  Straub's 
simple  method  is  for  many  purposes  the  best.  In  it  the  heart  receives  the 
nutrient  solution  through  a  simple  funnel  cannula  from  a  column  of  fluid  of  a 
minimal  height  of  2-3  cm.  By  its  own  beats  it  keeps  the  fluid  well  mixed  and 
may  continue  actively  beating  for  hours. 

For  the  pharmacologist  William's  frog-heart  apparatus  (Fig.  18) 
the  most  useful.    By  means  of  artificial  valves,  which  take  the  place 


240  PHARMACOLOGY  OF  CIRCULATION 

of  the  cardiac  valves,  the  nutrient  solution  circulates  in  this  apparatus 
through  a  rigid  system  of  tubes'  under  pressure  conditions  which  may 
be  altered  at  will. 

Two  glass  reservoirs  of  about  30  c.c.  capacity  are  used  as  containers  for 
the  normal  solution  and  for  the  solution  containing  the  drug.  The  rubber  tubes 
from  these  are  joined  together  by  a  Y-tube,  through  which  either  solution  may  be 
conducted  through  the  valve  of  ingress  to  a  double  cannula  which  leads  into  the 
ventricle.  The  other  branch  of  this  cannula  is  connected  with  a  second  valve, 
which,  like  the  aortic  valve,  keeps  the  solution  from  flowing  back  into  the  ven- 
tricle but  permits  it  to  return  to  the  reservoir.  A  manometer  is  connected  to 
that  part  of  the  system  which  represents  the  arterial  system.  By  narrowing 
or  widening  the  point  of  exit  from  this  system,  the  pressure  may  be  varied  at 
will  in  this  tube  which  represents  the  aorta. 

As  soon  as  the  necessary  resistance  is  produced,  each  heart-beat  causes  a 
certain  rise  in  pressure  in  the  manometer.  If  this  resistance  to  the  outflow  be 
kept  constant,  a  change  of  the  mean  pressure  or  in  the  size  of  the  pulse  in  the 
fixed  system  of  tubes  can  be  the  result  only  of  a  change  in  the  functional  activity 
of  the  heart.  With  this  apparatus  the  pulse  volume  of  the  heart  may  be  deter- 
mined either  by  measurement  of  the  fluid  pumped  out  or  by  plethysmographically 
recording  the  changes  in  volume  between  the  systolic  and  diastolic  phases  of  the 
ventricle.  The  work  done  by  the  heart  may  at  any  time  be  calculated  either 
for  the  unit  of  time  or  for  the  individual  heart-beat,  for  the  work  done  is  the 
product  of  the  amount  pumped  out,  the  pulse  volume,  multiplied  by  the  pressure 
against  which  the  heart  empties  itself.  If  this  pressure  be  increased  by  raising 
the  outflow  point,  a  pressure  may  be  reached  which  the  heart  is  no  longer  able 
to  overcome.  Thus  the  absolute  power  or  strength  of  the  heart  is  determined 
(Dreser). 

BIBLIOGRAPHY 

Blasius:    Verhandl.  d.  Physikal.-med.  Ges.  zu  Wiirzburg,  1871,  vol.  2,  p.  49. 

Blasius:  Pfliiger's  Arch.,  1872,  vol.  5,  p.  153. 

Cyon:  Ber.  d.  Kgl.  Sachs.  Ges.  d.  Wiss.,  1866,  p.  256. 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  24,  p.  227. 

Kronecker,  H. :  Beitr.  zur  Physiol.,  Leipzig,  1874,  p.  173. 

Straub:  Biochem.  Ztschr.,  1910,  vol.  28,  p.  392. 

Williams:  Arch.  f.  exp.  Path.  u.  Pharm.,  1880,  vol.  13,  p.  1. 

EXPERIMENTS  ON  THE  ISOLATED  MAMMALIAN  HEART. — By  perfusing 
its  coronary  vessels  the  isolated  mammalian  heart  may  also  be  kept 
beating  for  hours.  By  this  method,  too,  or  by  the  method  of  Bering 
and  Bock  (see  below),  it  is  possible  to  study  the  action  of  drugs  on  the 
heart  while  excluding  any  actions  on  the  general  vascular  system. 

The  method  of  Bering  and  Bock  (Fig.  19)  is  as  follows: 

The  descending  aorta  and  both  subclavians  of  a  rabbit  are  ligated.  One 
carotid  having  been  connected  with  a  manometer,  from  the  other  the  blood  passes 
through  a  U-tube  into  the  jugular  vein.  The  pulmonary  vessels  are  left  undis- 
turbed, and  the  blood  passing  through  the  lungs  is  arterialized  and  enters  the 
left  heart.  It  then  passes  through  the  aorta  into  the  carotid,  through  the  glass 
tube  into  the  jugular,  through  which  it  then  flows  back  into  the  right  heart.  The 
glass  tube  thus  replaces  the  general  vascular  system,  but  in  it  the  resistance 
remains  constant.  The  pulmonary  circulation  is  not  disturbed,  but  this  may  be 
disregarded,  for  the  pulmonary  vessels  are  little  or  not  at  all  affected  even  by 
the  most  powerful  vasoconstricting  or  vasodilating  drugs  (Gerhardt).  The 
vascular  system  under  these  conditions  is  thus  represented  by  a  system  of  tubes, 
which  with  the  exception  of  the  coronary  vessels  must  maintain  a  constant 
resistance. 


METHODS  OF  INVESTIGATION 


241 


The  heart  is  physiologically  isolated,  so  that  any  change  in  blood- 
pressure  in  this  system  must  be  the  result  of  an  alteration  in  the 
cardiac  function. 

The  method  of  perfusion  of  the  surviving  mammalian  heart,  chiefly 
developed  by  Langendorff,  depends  on  a  fact  already  observed  by 
Ludwig,  who  found  that  even  an  isolated  mammalian  heart  may  survive 
and  continue  to  beat  if  the  coronary  vessels  be  perfused  at  body  tem- 
perature with  defibrinated  blood  or  other  appropriate  nutrient  solu- 
tions. Under  such  conditions  a  heart  may  continue  to  beat  for  hours 
if  kept  in  a  moist  chamber  and  under  proper  conditions. 

Langendorff  causes  the  blood  to  flow  into  the  aorta  under  pressure,  and, 
as  the  aortic  valve  remains  closed,  the  only  outlet  for  the  blood  is  through  the 
coronary  vessels,  from  which  it  flows  into  the  right  auricle,  leaving  the  heart 
here.  The  cavities  of  the  heart  remain  empty,  but  the  heart  beats  for  long 
periods  with  satisfactory  regularity  if  the  supply  to  the  coronary  vessels  is  suffi- 


Vena  jugularit. 


Right  heart 


.Aorta 


Left  heart 


eient  and  constant  and  if  the  temperature  be  maintained  constantly  at  the  right 
degree.  If  these  conditions  be  maintained,  any  changes  in  the  action  of  the 
heart  may  be  attributed  to  the  drug  which  is  perfused.  A  heart  perfused  accord- 
ing to  this  method  preserves  a  fairly  normal  excitability  of  both  its  muscular 
and  nervous  elements,  so  that  it  will  respond  to  both  vagus  and  accelerator 
stimulation  (Langendorff,  Bering,  Steinberg). 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41. 
Gerhardt:    Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  44. 
Bering,  H.  E.:  Pflilger's  Arch.,  1898,  vol.  72,  p.  163. 
Bering,  H.  E.:   Pfliiger's  Arch.,  1903,  vol.  99,  p.  245. 
Langendorff:   Pfldger's  Arch.,  1895,  vol.  61,  p.  291. 
Steinberg:   Ztschr.  f.  Biol.,  1908,  vol.  51. 
Hild:  Ztschr.  f.  rat.  Med.,  1846,  vol.  5. 

METHODS  FOR  STUDYING  PHARMACOLOGICAL  ACTIONS 
ON  THE  VESSELS 

The  pharmacological  investigation  of  surviving  vessels  is  also 
feasible,  for  the  vessels  of  organs  removed  from  the  body  and  properly 
perfused  with  appropriate  solutions  at  body  temperature  also  "sur- 

16 


242  PHARMACOLOGY  OF  CIRCULATION 

•vive"  for  a  considerable  period.  If  the  perfused  fluid  be  allowed  to 
flow  under  constant  pressure  through  the  arteries  of  such  organs  as 
the  kidney,  spleen,  or  an  extremity,  and  the  amount  flowing  out  in  a 
unit  of  time  be  noted,  any  increase  or  diminution  in  the  rate  of  flow 
can  be  due  only  to  a  change  in  the  calibre  of  the  vessels,  the  cause  of 
which  must  lie  in  the  vessel  walls  themselves. 

Mosso,  in  Ludwig's  laboratory,  making  use  of  the  method  of  perfusion, 
was  the  first  to  demonstrate  the  peripheral  action  of  a  drug  on  the  vessel  walls. 
It  must,  however,  not  be  forgotten  that  surviving  vessels  are  no  longer  under 
physiological  conditions,  even  when  perfused  with  defibrinated  blood,  which  is  so 
especially  suitable  for  the  maintenance  of  the  chemical  processes  in  the  tissues, 
for  the  blood  never  flows  through  a  surviving  organ  so  rapidly  as  it  would  in  the 
living  animal  under  like  conditions  of  pressure  and  inflow,  and  its  rate  of 
outflow  diminishes  progressively  with  the  lapse  of  time.  Moreover,  even  slight 
variation  in  the  composition  of  the  artificial  nutrient  solution  from  that  of  normal 
blood — for  example,  the  defibrinization — is  of  moment  here.  The  method  is  thus 
necessarily  one  attended  by  many  sources  of  error.  Perfusion  with  blood-free 
Ringer's  solution  gives  the  most  constant  results. 

Recently  a  new  experimental  method  has  been  devised  which  per- 
mits of  the  direct  observation  of  changes  in  the  tone  of  excised  circular 
strips  of  the  arteries.  By  proper  treatment  in  Ringer 's  solution  main- 
tained at  body  temperature,  isolated  vessels  may  be  maintained  for 
days  in  an  excitable  condition,  so  that  drugs  acting  peripherally  will 
exert  their  specific  action  on  such  material  (v.  Frey,  J.  B.  Meyer, 
Langendorff) . 

The  peripheral  actions  on  the  vessels  are,  however,  in  no  way  alone 
responsible  for  the  behavior  of  the  different  vascular  systems  in  the 
living  body,  where  they  are  under  the  influence  of  the  central  nervous 
system  and,  as  previously  stated,  are  often  influenced  by  various  com- 
pensatory regulations.  Other  methods  (F.  Pick,  Biedl,  Barcroft  and 
Brodie')  are,  therefore,  needed  which  will  permit  the  determination 
intra  vitam  of  the  blood  flow  through  the  different  organs,  in  order 
that  we  may  determine  the  role  played  by  the  various  vascular  systems 
in  the  circulatory  changes  taking  place  throughout  the  body.  Here 
observations  of  the  outflow  from  veins  and  plethysmography  are  of 
value. 

A  plethysmogram  shows  the  changes  in  volume  taking  place  in  an 
organ  enclosed,  with  its  afferent  and  efferent  vessels,  in  an  air-tight 
container  constructed  especially  for  this  purpose.  Hoy,  using  his 
oncometer,  was  the  first  to  measure  the  volume  changes  of  the  kidney, 
but  at  the  present  time  Schaefer's  plethysmographs  are  usually  used. 
If  the  container  is  connected  with  an  apparatus  for  registering 
changes  of  volume,  such  as  the  piston  recorder,  the  separate  pulse- 
waves  are  visible,  the  increase  of  volume  of  the  organ  caused  by  each 
heart-beat  driving  air  out  of  the  oncometer.  In  the  same  fashion  the 
volume  of  the  enclosed  organ  follows  the  changes  in  blood-pressure 
during  longer  periods,  the  vessel  being  passively  dilated  by  increased 
blood-pressure  or  less  completely  filled  as  the  pressure  falls. 


METHODS  OF  INVESTIGATION  243 

Thus,  the  plethysmographic  curve  moves  in  the  same  direction  as  the 
blood-pressure  curve  if  the  vessels  in  the  enclosed  organ  are  not  themselves 
influenced  by  the  drug  employed.  If  these  vessels,  however,  are  contracted,  the 
volume  of  the  organ  does  not  increase,  but,  on  the  contrary,  diminishes,  as  the 
blood-pressure  rises,  and  the  two  curves  move  in  opposite  directions;  while,  on 
the  other  hand,  if  the  enclosed  vessels  actively  dilate,  the  plethysmographic  curve 
rises,  although  the  blood-pressure  remains  constant  or  even  if  it  falls,  and  thus 
this  curve  may  cross  the  blood-pressure  curve.  In  Fig.  20  is  seen  a  plethysmo- 
graphic curve  obtained  from  a  loop  of  gut  enclosed  in  a  plethysmograph.  This 
shows  the  changes  in  the  volume  of  the  intestines  during  stimulation  of  the 
splanchnic  nerve.  This  method,  as  also  the  outflow  method,  permits  of  the  simul- 
taneous determination  of  the  blood  flow  through  several  organs  and  of  their 
influence  on  each  other.  Pharmacological  vasomotor  actions  may  also  be  analyzed 
after  section  of  the  vasomotor  nerves,  and  in  such  experiments  electric  stimula- 
tion of  these  nerves  is  often  employed. 


Volume  (if  intestine 


D.P 


Stim.  of  splanchnic 


U  '  '    '   I   I   I    I   I   I   I   |   |   |   |   |   |   |   I   I   I   I   |   I    I    I   I   I   I    I   I   I   I    I   I   I   I   I   I  I 

FIG.  20. — Effect  on  intestine  of  stimulation  of  the  splanchnic  (Lehndorff). 

BIBLIOGRAPHY 

Barcroft  and  Brodie:  Journ.  of  Physiol.,  1905,  vol.  32,  p.  18. 

Biedl:   Pfluger's  Arch.,  1897,  vol.  67,  p.  446. 

Brodie:    Journ.  of  Physiol.,  1903,  vol.  29,  p.  266. 

Frey:  Sitz.-Ber.  d.  Physikal.-med.  Ges.,  Wiirzburg,  1905. 

Langendorff:    Zentralbl.  f.  Physiol.,  1908,  vol.  21,  No.  17. 

Lehndorff,  Arno:  Engelmann's  Arch.,  1908,  p.  362. 

Meyer,  J.  B. :  Ztschr.  f .  Biol.,  1907,  vol.  30,  p.  352. 

Mosso:   Physiol.  Anstalt  zu  Leipzig,  1874,  p.  305. 

Pfaff  u.  Vejnx-Theyrode:   Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  49,  p.  324. 

Pick,  F.:    Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42,  p.  399. 

Roy:  Journ.  of  Physiol.,  1881,  vol.  3,  p.  203. 

Schafer  and  Moore:  Journ.  of  Physiol.,  1896,  vol.  20,  p.  5. 


244  PHARMACOLOGY  OF  CIRCULATION 


PHARMACOLOGY  OF  THE  HEART 

All  the  factors  necessary  to  its  activity  are  contained  within  the 
heart  itself.  Normally  the  stimuli  for  the  automatic  cardiac  move- 
ments in  the  frog's  heart  originate  in  the  sinus  venosus,  and  in  the 
mammalian  heart  at  the  mouth  of  the  great  veins  (Adam),  the  rhythm 
of  the  heart  being  normally  determined  at  these  points, — that  is, 
the  motor  stimuli  for  the  heart  are  here  transformed  into  rhythmic 
stimuli  ( Gaskill  and  Engelmann) .  The  function  of  these  motor  centres 
in  the  heart  may  be  variously  influenced  by  drugs  and  poisons. 

A  brief  explanation  of  the  frequently  observed  vital  phenomenon  known  as 
rhythm  (Steinach)  may  aid  in  our  understanding  of  these  points.  One  of  the 
comparatively  few  established  and  fundamental  properties  of  all  nervous  centres 
(either  ganglia  or  nerve-plexuses)  is  their  power  to  summate  continually  arriving 
stimuli  and  thus  to  make  them  effective.  After  a  certain  period  this  summation 
results  in  a  discharge  of  energy  from  the  nervous  organ,  which  is  succeeded  by  a 
phase  of  exhaustion,  during  which  the  centres  remain  refractory — that  is,  insus- 
ceptible to  stimulation — until  sufficient  energy  has  again  been  developed  in  them, 
catabolic  and  anabolic  processes  thus  alternating.  This  periodicity  of  function 
in  the  centres  has  as  its  visible  effect  the  periodic  activity  of  the  organs  under 
their  control, — e.g.,  the  respiratory  muscles,  the  heart,  etc.  For  such  centres  as 
are  normally  constantly  called  upon,  this  refractory  phase  is  a  vital  necessity, 
enabling  them  to  develop  again  the  energy  needed. 

The  fundamental  work  of  Gaskell  and  Engelmann  has  demon- 
strated that  in  the  study  of  cardiac  activity  we  must  differentiate  be- 
tween the  different  cardiac  functions  which  are  involved,  as  these 
may  be  separately  affected  by  different  pharmacological  agents.  The 
frequency  with  which  stimuli  pass  to  other  portions  of  the  heart  is 
normally  controlled  by  the  state  of  the  stimulus-producing  mechanism 
in  the  sinus  (chronotropic  or  retarding  influence  of  the  sinus).  This 
mechanism  determines  the  rhythmic  activity  of  the  heart,  which  is  the 
first  of  its  physiological  characteristics  to  be  considered. 

It  may  further  be  shown  that  such  stimulus-inaugurating  mechanisms  exist 
not  only  at  the  situations  mentioned  but  also  in  all  parts  of  the  heart.  However, 
the  automatism  of  the  lower  portions  of  the  heart  is  only  latent, — that  is,  it 
remains  inactive  as  long  as  the  controlling  mechanism  in  the  sinus  is  active 
and  inhibits  these  secondary  ones.  This  is  analogous  to  the  phenomena  of  intra- 
central  inhibition  in  the  central  nervous  system. 

The  functional  activity  of  the  ventricles  is  controlled  and  may  be 
pharmacologically  influenced  by  the  following  factors: 

1.  The  power  of  rhythmical  activity  of  the  stimulus-producing 
mechanism  in  the  sinus, — chronotropic  function. 

2.  The  rate  of  conduction  of  stimuli  in  the  heart, — dromotropic 
function. 

3.  The    functional    capacity    of    the    excitable  peripheral    motor 
mechanism  in  the  heart  (nerves  or  muscles'), — bathmotropic  function. 

4.  The  momentary  internal  condition  of  the  heart  muscle,  which 
alone,  quite  independently  of  the  strength  of  the  stimulus,  determines 
the  extent  and  power  of  the  contraction, — inotropic  function. 


PHARMACOLOGY  OF  THE  CARDIAC  NERVES        245 

All  these  different  functional  attributes  of  the  heart  are  sus- 
ceptible of  influence  through  both  the  extracardial  and  the  intracardiac 
nerves,  the  heart  receiving  from  the  central  nervous  system  a  double 
nerve  supply,  the  inhibitory  vagus  from  the  cranial  autonomic  para- 
sympathetic  system  and  the  accelerator  fibres  from  the  sympathetic 
system.  Both  nerves  may  be  acted  upon  by  drugs  at  their  points  of 
origin  in  the  central  nervous  system  as  well  as  peripherally  in  the 
heart. 

BIBLIOGRAPHY 

Adam:   Pfliiger's  Arch.,  1906,  vol.  Ill,  p.  607. 

Steinach :   Pfliiger's  Arch.,  1908,  vol.  125,  pp.  239  and  290. 

PHARMACOLOGICAL  ACTIONS    ON   THE   EXTRACARDIAL   NERVES 

THE  INHIBITORY  CENTRE  IN  THE  MEDULLA  is  directly  stimulated 
by  a  number  of  agents,  the  best-known  example  of  this  being  its 
stimulation  by  the  blood  of  asphyxia.  Certain  medullary  convulsants 
(Krampfgifte),  such  as  picrotoxin  and  cicutoxin,  like  asphyxia,  simul- 
taneously stimulate  the  vagus  and  the  vasomotor  centres  (Bohm). 
Epinephrin  (Verworn,  Biedl  u.  Reiner)  and  the  digitalis  group 
(Kochmann)  also  directly  stimulate  the  vagus  centre  independently 
of  their  indirect  actions  on  it.  However,  in  the  case  of  those  sub- 
stances which  cause  a  rise  in  blood-pressure,  as  also  in  asphyxia,  it  is 
extremely  difficult  to  distinguish  between  a  direct  stimulation  of  the 
vagus  centre  and  an  indirect  stimulation  resulting  from  the  rise  in 
blood-pressure. 

As  shown  by  Bernstein,  the  tone  of  the  vagus  centre  depends  on  the 
height  of  the  blood-pressure,  it  being  augmented  by  a  rise  in  blood- 
pressure,  such  as  that  caused  by  a  temporary  overfilling  of  the  arterial 
system,  while  during  a  fall  in  blood-pressure,  such  as  follows  hemor- 
rhage, the  pulse  becomes  more  rapid,  the  vagus  centre  being  rendered 
less  susceptible  to  reflex  influences.  It  therefore  follows  that  the  rate 
of  the  heart  is  altered  secondarily  by  all  pharmacological  agents  which 
raise  or  lower  the  general  blood-pressure.  Thus,  the  pulse  is  slowed 
by  the  rise  in  blood-pressure  produced  by  strychnine  and  accele- 
rated by  the  fall  caused  by  amyl  nitrite,  although  these  drugs  have 
no  direct  action  on  the  vagus  centre. 

As  is  well  known,  section  of  the  vagi  is  followed  by  more  or  less 
pronounced  acceleration  of  the  pulse,  this  being  due  to  the  abolition 
of  the  restraining  influence  of  this  centre,  and  varying  in  intensity 
according  to  the  species  of  animal  in  question.  It  is  self-evident  that 
after  section  of  the  vagi  there  can  be  no  slowing  of  the  pulse  through 
any  stimulation  of  this  centre  by  drugs  or  other  agents.  Paralysis 
of  the  vagus  centre  by  drugs  or  poisons  produces  the  same  results  as 
section  of  the  nerves,  and  causes  a  corresponding  acceleration  of  the 
pulse,  which  varies  in  extent  with  the  animal  observed. 

Acceleration  of  the  pulse  may  also  be  due  to  stimulation  of  the 
accelerator  centres. 


246  PHARMACOLOGY  OF  CIRCULATION 

The  acceleration  of  the  pulse  preceding  vomiting  is  an  example  of  the 
effect  of  such  accelerator-centre  stimulation.  Further,  the  blood  of  asphyxia 
stimulates  this  centre  just  as  it  does  the  vagus  centre.  Therefore,  asphyxia 
of  a  curarized  animal  causes  acceleration  of  the  pulse  if  the  vagus  has  been 
eliminated  by  section  or  otherwise  (Dastre  et  Morat,  Konow  u.  Stenbeck).  So 
long  as  the  vagus  is  functioning,  the  effect  of  its  stimulation  outweighs  that  of 
the  accelerator  stimulation,  just  as  normally  the  vagus  tonus  is  more  powerful 
than  that  of  the  accelerator  ( Bering ) .  It  is  probable  that  a  central  accelerator 
stimulation  is  in  part  responsible  for  the  acceleration  of  the  pulse  which  follows 
the  primary  slowing  caused  by  the  medullary  stimulants,  picrotoxin  and  cicutoxin 
(Bohm) . 

The  peripheral  actions  of  drugs  on  the  vagus  and  the  accelerator 
are  readily  comprehensible  if  we  consider  the  general  principles  of 
pharmacological  action  on  the  vegetative  nervous  system.  In  accord- 
ance with  these  general  principles,  it  is  to  be  expected  that  the  inhibi- 
tory mechanism  will  be  influenced  by  those  agents  which  also  act  on 
the  other  autonomic  nerves,  and  that  the  accelerator  will  be  influenced 
by  those  affecting  the  sympathetic  system.  In  both  vegetative  systems 
the  seat  of  action  may  be  in  either  the  nerve-endings  or  the  inter- 
mediate ganglia. 

BIBLIOGRAPHY 

Biedl  u.  Reiner:    Pflfjger's  Arch.,  1898,  vol.  73,  p.  385. 

Bohm:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5,  p.  279. 

Bernstein:  Zentralbl.  f.  d.  Med.  Wiss.,  1867,  p.  1. 

Dastre  et  Morat:    Arch,  de  Physiol.,  1885. 

Filehne,  W.:  Pfliiger's  Arch.,  1874,  vol.  9,  p.  470. 

Hering,  H.  E.:  Pfliiger's  Arch.,  1895,  vol.  60,  p.  442. 

Kochmann:  Arch,  intern,  de  Pharmacodyn.  et  de  Therap.,  1905,  vol.  16. 

Konow  u.  Stenbeck:    Skand.  Arch.  f.  Physiol.,  1889,  vol.  1. 

Mayer:    Siegm.,  Sitz.-Ber.  d.  Wien.  Akad.  d.  Wiss.,  1872,  vol.  64. 

Mayer,  S.,  u.  Freidrich:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5,  p.  55. 

Verworn:  Engelmann's  Arch.  f.  Physiol.,  1903,  p.  65. 

DRUGS  ACTING  ON  THE  VAGUS  IN  THE  PERIPHERY. — The  same  drugs, 
whose  specific  action  on  the  autonomic  nerves  has  already  been  learned 
in  connection  with  their  action  on  the  intestines,  have  been  found  to 
have  similar  pharmacological  actions  on  the  peripheral  portion  or  the 
cardiac  vagus,  which,  as  we  know,  belongs  to  the  cranial  autonomic 
system.  Thus,  it  is  known  of  nicotine  that  it  for  a  time  stimulates  and 
then  depresses  the  ganglia  interposed  in  the  path  of  the  autonomic 
fibres.  This  is  the  explanation  of  that  peculiar  action  on  the  inhibitory 
cardiac  nerves  which  was  first  explained  by  Schmiedeberg. 

Action  of  Nicotine  on  the  Frog's  Heart. — If  a  small  amount  of  nicotine  be 
administered  to  a  frog,  the  heart  action  is  soon  slowed,  in  fact  it  quickly  comes 
to  a  rest  in  diastole.  This  stoppage  lasts  at  the  most  not  more  than  one 
or  two  minutes,  and  soon  the  heart  beats  again,  apparently  just  like  a  normal 
one.  However,  in  this  secondary  stage  the  inhibitory  mechanism  behaves  in  a 
peculiar  fashion,  for  if  the  vagus  nerve  trunk  be  stimulated  no  slowing  occurs. 
If  now  the  sinus  be  stimulated  or  muscarine  be  applied  to  the  heart,  it  quickly 
stops  in  diastole  and  remains  quiet.  The  nicotinized  heart  thus  reacts  to  mus- 


PHARMACOLOGY  OF  THE  CARDIAC  NERVES         247 

carine  or  to  sinus  stimulation  like  the  normal  organ,  but  to  vagus  stimulation 
like  an  atropinized  one.  The  action  of  the  nicotine  must,  therefore,  have  im- 
paired the  conductivity  of  some  part  of  the  inhibitory  mechanism,  a  part  through 
which  the  effective  vagus  stimulation  must  pass  but  which  lies  farther  from  the 
heart  than  the  point  at  which  sinus  stimulation  or  muscarine  acts.  This  portion 
has  been  named  by  Schmiedeberg  the  "intermediate  portion"  ( Zwischenstiick ) . 
According  to  the  general  laws  which  have  been  demonstrated  by  Langley  and 
Dickinson  for  the  action  of  nicotine  on  the  autonomic  ganglia,  it  may  be  concluded 
that  the  ganglia  interposed  in  the  vagus  fibres  lie  between  the  vagus  trunk  and 
its  nerve-endings. 

The  vagus  trunk  contains  the  preganglionic  fibres,  the  stimulation  of  which, 
according  to  the  rule,  is  ineffectual  after  administration  of  nicotine.  Stimulation 
of  the  sinus  affects  the  post-gangl  ionic  fibres,  whose  nerve-endings  are  acted  upon 
by  atropine  and  muscarine  but  not  by  nicotine. 

The  stellate  ganglion  is,  as  it  were,  a  relay  station  for  the  accelerator 
fibres,  for,  after  administration  of  nicotine,  the  post-ganglionic  accelerator  fibres 
— which,  in  the  frog  and  in  some  of  the  higher  species,  pass  down  in  the  vagus 
trunk — remain  excitable,  and,  therefore,  stimulation  of  the  vagus  still  causes 
an  acceleration  of  the  pulse  even  after  nicotine  has  been  administered  (Schmiede- 
berg). 

TOBACCO  POISONING. — In  man,  too,  the  pulse  is  unusually  rapid  in 
nicotine  poisoning,  this  being  due  to  prevention  of  the  central  vagus 
inhibition,  as  described  above.  Later  the  pulse  becomes  slower  as  a 
consequence  of  the  depressing  action  of  nicotine  on  the  automatic 
motor  mechanism  of  the  heart.  In  chronic  tobacco  poisoning,  irregular 
intermittent  heart  action  is  frequently  observed.  Acute  tobacco  poison- 
ing is,  however,  not  an  effect  of  nicotine  alone,  for  pyridine  and  a 
number  of  other  toxic  substances  also  play  a  role  in  producing  the 
effects  caused  by  smoking.  The  primary  slowing  and  later  the 
acceleration  of  the  pulse,  the  increase  of  secretions  and  the  increased 
peristalsis,  with  nausea  and  vomiting,  may,  however,  be  considered 
as  due  to  the  nicotine.  The  same  is  true  of  the  pallor  and  faintness 
which  are  due  to  central  depression. 

Pilocarpine  acts  in  a  similar  way  on  the  " intermediate  portion'* 
of  the  cardiac  inhibitory  mechanism,  causing,  in  the  frog,  slower  heart 
action  and  diastolic  standstill,  which  may  last  for  as  long  as  two 
minutes,  and  is  then  followed  by  more  rapid  heart  action  (Harnack  u. 
H.  Meyer} .  At  this  stage  stimulation  of  the  vagus  is  ineffectual,  but 
direct  stimulation  of  the  sinus  or  application  of  muscarine  to  it  results 
in  a  stoppage  of  the  heart.  With  the  higher  experimental  animals 
the  stage  of  slowing  passes  even  more  rapidly. 

Curare  and  many  other  drugs  have  a  similar  action  on  these  autonomic 
ganglia,  but  such  effects  are  produced  only  by  large  doses  (Langley  and  Anderson). 

BIBLIOGRAPHY 

Harnack  u.  H.  Meyer:    Arch.  f.  exp.  Path.  u.  Phann.,  1880,  vol.  12,  p.  366. 
Langley  and  Anderson:  Journ.  of  Physiol.,  1895,  vol.  19,  p.  139. 
Langley  and  Dickinson:  Journ.  of  Physiol.,  1890,  vol.  li,  p.  265. 
Schmiedeberg:   Ber.  d.  Sachs.  Akad.  d/Wiss.,  1870,  vol.  22,  p.  135. 


248  PHARMACOLOGY  OF  CIRCULATION 

Muscarine  and  atropine  act  on  the  ultimate  terminations  of  the 
vagus  (cranial  autonomic  nerve). 

Muscarine  is  an  alkaloid  obtained  from  one  of  the  common  poisonous 
mushrooms,  Amanita  muscaria,  or  Agaricus  muscarius,  or  fly  mushroom.  It 
was  first  isolated  by  Schmiedeberg  in  1868.  These  mushrooms  also  contain  a 
much  less  poisonous  base,  choline  (Harnack),  which  is  formed  by  the  decomposi- 
tion of  lecithine  and  which  is  a  constant  constituent  of  many  animal  tissues,  and 
is  chemically  designated  trimethyloxyethyl  ammonium  hydroxide, 


\) 


CO 


Muscarine  differs  from  this  in  its  composition  only  by  containing  one  more  atom 
of  oxygen,  and  is  probably  formed  from  choline  by  oxidation. 

In  fact,  by  allowing  fuming  nitric  acid  to  act  on  choline,  Schmeideberg  and 
Harnack  prepared  an  artificial  muscarine,  which,  although  similar  to,  is  not 
identical  with  the  muscarine  obtained  from  the  fly  mushrooms  (Bohm,  H.  Meyer)  . 
Its  pharmacological  actions,  while  resembling  those  of  the  natural  alkaloid,  are 
not  entirely  the  same,  for,  although  the  action  on  the  vagus  nerve-endings  is  the 
same,  it,  on  the  other  hand,  causes  paralytic  phenomena  resembling  those  result- 
ing from  the  administration  of  curare. 

Choline  also  has  a  pronounced  muscarine-like  action  on  the  vagus 
nerve-endings,  a  fact  which  may  be  of  some  physiological  significance, 
inasmuch  as  it  has  recently  been  shown  that  choline  is  a  constant  con- 
stituent of  many  tissues.  It  may  well  be  that  the  variable  amounts 
present  under  different  conditions  may  exert  an  influence  on  the 
activity  of  the  vagus  nerve-endings. 

Muscarine  on  the  Frog's  Heart.  —  If  a  small  amount  of  muscarine 
be  injected  into  a  frog,  the  heart  promptly  begins  to  beat  more  and 
more  slowly,  and  finally  stands  still  in  a  state  of  maximal  diastolic 
relaxation,  the  auricles  usually  stopping  first.  This  is  not  due  to  a 
paralysis  of  the  heart,  for  any  mechanical  or  electrical  stimulation  of 
the  ventricle  causes  a  prompt  contraction.  In  fact,  the  heart  is  more 
susceptible  to  such  stimuli  than  is  normally  the  case  at  the  end  of  the 
usual  short  diastole.  The  excitability  of  the  motor  centres  and  the 
power  of  the  muscles  to  contract  are  both  preserved,  although  inhibited. 
The  antagonistic  action  of  atropine  shows  us  the  seat  of  action  of  this 
peculiar  pharmacological  effect.  It  has  long  been  known  that  stimula- 
tion of  the  cervical  vagus  is  ineffectual  after  small  doses  of  atropine 
(v.  Bezold,  Schmiedeberg}.  Similarly  muscarine  no  longer  causes  a 
slowing  or  stopping  of  the  heart  if  atropine  has  been  previously 
applied. 

In  the  frog's  heart  muscarine  produces  the  same  effect  as  a  con- 
tinuous vagus  stimulation.  By  the  electric  stimulation  of  the  inhibi- 
tory fibres,  the  number  of  beats  is  lessened,  the  systolic  contractions 
are  rendered  less  complete,  and  the  diastolie  distention  is  increased.  In 
certain  cases  the  number  of  beats  is  markedly  lessened,  the  pulse 


PHARMACOLOGY  OF  THE  CARDIAC  NERVES         249 

volume  of  the  heart  remaining  about  normal,  while  in  other  cases  the 
heart  rate  is  little  affected  but  the  systolic  contractions  become  very 
incomplete.  While  this  holds  true  for  the  effects  of  small  doses  of  mus- 
carine  (Cushny),  with  larger  doses  the  heart  rate  is  always  markedly 
slowed  and  the  diastolic  relaxation  strikingly  augmented,  or  else  the 
heart  remains  permanently  relaxed.  Muscarine,  like  vagus  stimulation, 
is  thus  seen  to  be  negatively  chronotropic  (retarding)  and  negatively 
inotropic  (weakening). 

If  the  heart  of  a  cold-blooded  animal  be  perfused  with  a  solution  containing 
muscarine,  the  typical  slowing  and  stoppage  result,  but  after  a  time  the  heart 
begins  to  beat  again,  although  at  this  period  the  heart  contains  enough  muscarine 
to  stop  another  heart.  If,  after  the  heart  has  begun  to  beat  again,  still  more 
muscarine  be  added  to  the  perfused  fluid,  the  same  succession  of  events  occurs, 
the  heart  stopping  once  more,  but  after  a  time  beginning  to  beat  again.  It  is 
thus  evident  that  it  is  not  the  presence  in  the  heart  of  a  certain  amount  of 
muscarine  which  excites  the  inhibitory  mechanism,  but  that  the  stimulus  to  the 
inhibition  is  caused  by  the  process  of  permeation,  the  muscarine  "  pressure " 
(Gefalle)  (Straub).  In  the  case  of  other  pharmacological  actions  on  the  heart — 
for  example,  that  of  the  digitalis  group — the  effective  factor  is  not  the  pressure 
produced  during  permeation,  but  is  their  combination  with  specifically  susceptible 
elements, — that  is,  an  alteration  of  physiological  conditions. 

Loewi  has  shown  that  the  negative  inotropic  effects  of  muscarine 
may  be  promptly  overcome  by  calcium  salts,  while  all  of  its  effects  are 
promptly  suppressed  by  the  smallest  doses  of  atropine,  so  that  the 
heart  beats  like  a  normal  one,  and  previous  application  of  atropine 
prevents  the  development  of  any  muscarine  action. 

While  a  complete  suppression  of  the  muscarine  action  may  be  effected  only 
by  the  use  of  atropine,  a  number  of  substances  which  stimulate  the  cardiac  motor 
mechanism  cause  the  diastolic  standstill  to  be  interrupted  by  more  or  less 
frequent  beats.  While  atropine  abolishes  all  the  characteristic  changes  in 
function  produced  by  muscarine,  the  diastolic  character  of  the  heart  action  per- 
sists after  the  incomplete  antagonistic  effects  resulting  from  the  action  of  these 
other  substances,  the  inhibition  continuing,  but  being  interrupted  from  time  to 
time  on  account  of  the  increased  excitation  of  the  motor  elements.  In  this  way 
a  muscarinized  heart  may  be  used  as  a  means  of  testing  a  stimulating  effect  due 
to  action  on  the  motor  elements. 

BIBLIOGRAPHY 

v.  Bezold:  Untersuch.  d.  Physiol.  Labor.,  Wtirzburg,  vol.  1. 

Bohm:  Arch.  f.  exp.  Path.  u.  Pharm.,  1885,  vol.  19,  p.  87. 

Cushny:  Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  vol.  31,  p.  431. 

Harnack:  Arch.  f.  exp.  Path.  u.  Pharm.,  1875,  vol.  4,  p.  168. 

Loewi:  Zentralbl.  f.  Physiol.,  1905,  vol.  19,  p.  593. 

Meyer,  H.:    Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  vol.  32,  p.  101. 

Schmiedeberg:  Ber.  d.  Sachsisch.  Ges.  d.  Wiss.,  1870. 

Schiniedeberg  u.  Harnack:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  6,  p.  101. 

Schmiedeberg  u.  Koppe:  Das  giftige  Alkaloid  des  Fliegenpilzes,  Leipzig,  1869. 

Straub:  Pflfiger's  Arch.,  1907,  vol.  119,  p.  127. 

ATROPINE. — Small  doses  of  atropine  have  as  their  sole  cardiac 
action  that  of  depressing  those  vagal  nerve-endings  which  are  stimu- 
lated by  muscarine.  According  to  Harnack  and  Hafemann,  1/50  nag. 


250  PHARMACOLOGY  OF  CIRCULATION 

to  50  cm.  of  perfusion  fluid  is  sufficient  to  produce  this  result,  so  that 
it  is  then  impossible  to  cause  inhibition  of  the  heart  by  either  vagus 
or  sinus  stimulation,  or  by  muscarine,  nicotine,  or  pilocarpine.  In 
other  respects  the  heart  behaves  normally.  The  following  curve  shows 
the  effects  of  small  doses  of  atropine  in  overcoming  the  muscarine 
standstill  of  the  frog's  heart,  suspended  according  to  the  method  of 
Gaskell  and  Englemann: 

T        Muscarine    normal 


Fio   21.  —  Suppression  of  the  muscarine  standstill  by  atropine.    Read  from  right  to  left. 

In  addition  to  their  depressing  action  on  the  inhibitory  mechanism,  larger 
doses  of  atropine  would  appear  also  to  exert  stimulating  effects  on  the  motor 
mechanism  of  the  heart.  In  Langendorff's  experiments,  atropine  exerted  a 
positively  chronotropic  influence  on  the  secondary  automatic  motor  centres  which 
lie  in  the  apex  of  the  frog's  heart.  After  functional  separation  from  the  higher 
controlling  centres  by  clamping,  the  apex  under  ordinary  conditions  remains 
inactive.  After  application  of  atropine,  however,  contractions  of  the  apex  may 
occur  spontaneously,  or  a  mechanical  stimulus  causes  a  long  series  of  beats, 
although  an  unatropinized  apex  responds  to  each  stimulus  with  but  one  con- 
traction. We  are  dealing  here  with  an  exciting  action  of  atropine  in  doses  which 
are  many  times  larger  than  those  which  completely  paralyze  the  inhibitory 
apparatus  (Hedbom).  The  often-claimed  suppression,  by  such  larger  doses,  of 
the  standstill  of  the  heart,  due  not  to  inhibition,  but  to  paralysis  of  the  motor 
mechanism  (Luchsinger),  does  not  affect  the  value  which  small  doses  of  atropine 
possess  as  a  certain  test  for  inhibitory  actions.  A  standstill  of  the  heart  or  a 
slowing  of  the  pulse  which  is  removed  by  small  doses  of  atropine  is  due  to 
inhibition. 

The  stimulation  of  the  cardiac  inhibitory  mechanism  by  muscarine 
and  its  depression  by  atropine  occur  also  in  the  mammal,  in  a  fashion 
quite  analogous  to  the  above-described  effects  on  the  frog's  heart. 
Stoppage  of  the  heart  or  an  extreme  slowing  of  the  pulse  by  muscarine 
necessarily,  however,  causes  much  more  violent  symptoms  in  the  warm- 
blooded animal,  on  account  of  the  secondary  effects  resulting  from 
disturbed  circulation.  After  a  muscarine  injection  the  aortic  pressure 
sinks  rapidly  (Fig.  22).  During  the  longer  or  shorter  diastolic  pauses 
the  heart  is  maximally  distended,  only  incomplete  contractions  inter- 
rupting the  standstill.  Inasmuch  as  the  blood  cannot  pass  from  the 
greater  veins  into  the  overfilled  auricles,  the  blood  accumulates  in  the 
pulmonary  system,  and  dyspnea  must  quickly  result,  for  the  over- 
filling of  the  pulmonary  vessels  interferes  with  the  air-change  and 
at  the  same  time  the  circular  muscles  are  tonically  contracted.  The 
asphyxia  must  quickly  prove  fatal  if  a  dose  of  atropine  does  not 
relieve  it.  Atropine  may  also  overcome  the  marked  pulse  slowing, 
and  if  the  heart  has  not  been  too  much  harmed  by  the  asphyxia  it 
quickly  recovers.  Previous  section  of  the  vagi  causes  no  alteration 
in  the  phenomena  resulting  from  the  administration  of  the  muscarine. 


PHARMACOLOGY  OF  THE  CARDIAC  NERVES 


251 


Of  importance  in  connection  with 
the  poisoning  produced  by  the  fly 
mushrooms  is  a  base  resembling 
atropine  (Schmiedeberg) ,  as  well  as 
another  poison  still  imperfectly  in- 
vestigated, which  produces  symptoms 
of  excitation  of  the  central  nervous 
system  and  which  is  found  chiefly 
in  the  fresh  mushrooms  (Harmsen). 
[A  glucoside  studied  by  Ford  and 
Abel  and  possessing  many  interest- 
ing properties  would  appear  also  to 
be  of  considerable  importance  in 
this  connection. — TR.]  As  a  result 
of  the  combined  action  of  these  dif- 
ferent poisons,  the  symptoms  of 
mushroom  poisoning  differed  mark- 
edly from  those  observed  in  poisoning 
by  pure  muscarine  in  the  animals. 

Muscarine  Poisoning. — The  symptom 
complex  of  muscarine  poisoning  results 
from  its  actions  on  the  stomach  and  intes- 
tines, already  described  in  a  previous  sec- 
tion, and  from  those  on  the  eye  and  on  the 
secretions,  and  especially  from  the  actions 
on  the  circulation  which  threaten  the  life 
of  the  victim.  It  is  especially  well  devel- 
oped in  the  cat.  The  first  symptoms — 
namely,  chewing  and  licking  movements, 
with  flow  of  saliva — develop  within  a  few 
minutes  after  the  subcutaneous  injection 
of  several  milligrammes.  Active  peri- 
stalsis, retching,  vomiting,  defecation,  and 
tenesmus  ensue,  as  well  as  contraction  of 
the  pupil,  leading  perhaps  to  its  complete 
disappearance.  The  pulse  becomes  ex- 
tremely slow,  marked  dyspnoea  develops, 
and  the  animal  can  no  longer  maintain  the 
upright  position,  but  falls  on  its  side,  death 
with  light  convulsions  resulting  from  stop- 
page of  the  respiration  at  a  time  when 
occasional  heart-beats  still  occur.  Atro- 
pine may  rescue  the  animal,  even  in  ex- 
tremis, and  this  drug  is  probably  the  proper 
antidote  in  mushroom  poisoning  in  man,  as 
well  as  in  poisoning  by  certain  little- 
known  ptomaines  formed  during1  putrefac- 
tion, which  have  a  muscarine-like  action. 

PHYSOSTIGMINE.  —  During  our 
study  of  the  action  of  physostigmine 
on  the  intestines  and  on  the  pupils, 
we  have  learned  that  it  is  a  drug 
which  stimulates  vagus  nerve-endings 


252  PHARMACOLOGY  OF  CIRCULATION 

(Winterberg)  and  slows  the  pulse.  As  this  effect  is  not  completely  sup- 
pressed by  atropine,  it  follows  that  physostigmine  must  act  on  the  heart 
at  a  different  point  from  atropine,  but  the  situation  of  this  point  has 
not  yet  been  definitely  determined  (Winterberg,  E.  Harnack). 

ACTIONS  ON  THE  ACCELERATOR  IN  THE  PERIPHERY. — The  nerve- 
endings  of  the  accelerator  nerves  are  part  of  the  sympathetic  system, 
and,  like  all  the  nerve-endings  of  this  system,  they  too  are  stimulated 
by  epinephrin.  Cocaine's  similar  behavior  toward  the  sympathetic 
system  has  already  been  discussed,  and  the  acceleration  of  the  pulse 
at  the  commencement  of  the  cocaine  action  has  been  recognized  as 
a  side  action  of  this  drug.  The  influence  of  epinephrin  on  the 
intracardiac  accelerator  nerve-endings  appears  clearly  in  the  isolated 
heart  prepared  according  to  Langendorff 's  method.  Its  effects  on  the 
intact  circulation  are  complicated  by  the  retardation  of  the  pulse 
resulting  from  the  already-mentioned  stimulation  of  the  vagus  centre. 
In  fact,  at  the  start  this  slowing  preponderates. 

The  increase  in  pulse-rate  after  the  administration  of  caffeine  or 
theobromine  is  also  due  to  excitation  of  the  accelerator  nerve-endings. 
This  may  be  seen  in  susceptible  individuals  after  drinking  strong 
coffee. 

It  may  further  be  stated  that  it  is  not  possible  to  differentiate 
between  actions  on  the  accelerator  nerve-endings  and  the  alterations 
in  function  of  those  mechanisms  in  the  heart  which  we  have  defined 
as  the  "stimulus-producing  mechanisms,"  and  which  from  now  on 
will,  in  the  interest  of  brevity,  be  spoken  of  as  the  ''motor  centres." 
These  centres  in  the  heart  are  either  identical  with  the  accelerator 
nerve-endings — H.  E.  Hering  was  able  by  stimulation  of  the  accelerator 
to  cause  the  dog's  heart,  perfused  according  to  Langendorff,  again  to 
beat  automatically  after  it  had  entirely  ceased  to  beat — or  at  least 
we  are  unable  at  present  to  distinguish  between  the  accelerator  nerve- 
endings  and  the  motor  apparatus  of  the  heart.  For  these  reasons  the 
above-discussed  pharmacological  actions  on  the  terminal  portions  of 
the  accelerator  nerves  must  also  be  considered  as  actions  on  the  motor 
centres  of  the  heart. 

BIBLIOGRAPHY 

Harmsen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  50,  p.  361. 
Harnack,  E.:   Ztschr.  f.  exp.  Path.  u.  Therap.,  1908,  vol.  5. 
Hedbom:   Skand.  Arch.  f.  Physiol.,  1899,  vol.  9,  p.  1. 
Hering,  H.  E.:    Pfliiger's  Arch.,  1905,  vol.  115,  p.  354. 
Luchsinger:  Arch.  f.  exp.  Path.  u.  Pharm.,  1881,  vol.  14. 
Schmiedeberg:  Arch.  f.  exp.  Path.  u.  Pharm.,  1881,  vol.  14,  p.  376. 
Winterberg:  Ztschr.  f.  exp.  Path.  u.  Therap.,  1907,  vol.  4. 

CARDIAC  DEPRESSANTS 

The  number  of  these  is  legion.  In  them  are  included,  among  othei 
the  narcotics  of  the  aliphatic  series,  of  which  those  containing  halogen 
are  distinctly  more  harmful  to  the  heart  than  those  containing  no 


CARDIAC  DEPRESSANTS  253 

halogens.  Using  the  isolated  frog's  heart,  Dieballa  has  investigated 
quantitatively  the  activity  of  the  different  members  of  this  group,  and 
has  ascertained  that  chloroform  exceeds  in  its  heart-depressing  action 
all  the  other  members  of  this  group  which  were  investigated.  In  order 
to  produce  the  same  cardiac  effects  as  produced  by  chloroform,  it  is 
necessary  to  use  of  ethyl  bromide  12  times  the  molecular  concentration, 
of  ether  48  times,  and  of  alcohol  132  times.  Bock's  experiments  with 
the  "  heart-lung-circulation "  resulted  in  an  equally  indisputable 
demonstration  of  the  enormous  difference  in  the  toxicity  for  the  heart 
of  chloroform  and  ether. 

Numerous  other  substances  belonging  to  different  pharmacological 
groups  have  a  similar  power  of  causing  retardation  of  the  pulse  and 
depression  of  the  heart,  which  results  finally  in  stoppage  of  the  heart 
in  diastole.  According  to  Brandenburg,  the  salts  of  the  bile  acids  must 
be  included  here,  although'  these  slow  the  heart  also  through  action 
on  the  vagus  centres  (Loewi,  Weintraud}.  With  more  pronounced 
pharmacological  action,  however,  they  directly  affect  the  production 
of  stimuli  in  the  heart.  This  is  of  importance  in  connection  with  the 
slowing  of  the  pulse  in  icterus,  as  this  must  be  attributed  to  their 
direct  cardiac  depressant  action  as  well  as  to  the  central  stimulation 
of  the  vagus  produced  by  them.  Atropine  usually  overcomes  the 
pulse-slowing  in  icterus,  as  was  demonstrated  by  Weintraud  in  a  series 
of  cases.  This,  however,  does  not  exclude  the  possibility  that  a 
depression  of  the  motor  apparatus,  which,  is  not  influenced  by 
atropine,  may  occur  clinically  as  a,  second  component  of  the  toxic 
action  resulting  from  the  presence  in  the  blood  of  larger  amounts  of 
these  salts,  just  as  is  the  case  when  either  the  frog's  or  the  isolated 
mammalian  heart  is  poisoned  by  larger  doses. 

With  the  aid  of  atropine  it  is  possible  to  distinguish  between 
pulse-slowing  due  to  stimulation  of  the  inhibitory  mechanism  and 
that  resulting  from  depression  of  the  motor  mechanism.  On  the 
other  hand,  it  is  much  more  difficult  to  differentiate  between  a  depres- 
sion of  the  automatic  motor  centres  in  the  heart  and  a  depression  of  the 
contractile  power  of  the  cardiac  muscles.  Negative  chronotropic  and 
negative  inotropic  pharmacological  actions  usually  go  together,  and 
soon  after  the  cessation  of  its  automatic  activity  the  heart  loses  its  ex- 
citability to  mechanical,  electrical,  and  chemical  stimuli.  This  is  the 
case,  for  example,  after  large  amounts  of  quinine  (Santessori).  The 
potassium  salts  are  also  typical  cardiac  depressants  if  under  certain 
conditions  (intravenous  injections  or  subcutaneous  administration  of 
very  large  quantities)  their  concentration  in  the  blood  is  increased 
beyond  0.08  per  cent.  (Tetens).  In  this  case,  too,  loss  of  excitability 
of  the  muscles  follows  quickly  on  the  cessation  of  contractions. 

Chloral  hydrate  is  a  type  of  the  cardiac  depressants.  Under  its 
influence  the  heart  beats  slower  and  slower,  and  during  its  prolonged 

itole  is  more  relaxed  and  distended  than  normally.    Shortly  after 


254  PHARMACOLOGY  OF  CIRCULATION 

stoppage  in  diastole  has  occurred,  each  mechanical,  chemical,  or  elec- 
trical stimulus  results  in  a  contraction,  but  atropine  does  not  over- 
come this  standstill.  In  their  physiological  analysis  of  this  progressive 
pulse-slowing,  Harnack  and  Witkowski  were  able  to  determine  that 
the  seat  of  action  of  the  paralysis  lay  in  the  automatic  mechanism  of 
the  heart,  for  the  rate  of  the  whole  heart  was  slowed  by  painting  the 
sinus  with  chloral  or  the  similarly  acting  iodal.  Later  a  depression 
of  the  power  of  contraction  also  occurred.  It  is  thus  seen  that  the 
primary  action  of  chloral  hydrate  is  negatively  chronotropic,  and, 
more  weakly  and  usually  somewhat  later,  it  is  also  negatively  inotropic. 
The  excitability  and  the  conduction  of  stimuli  are  less  affected 
(Bohme),  and  it  may  in  general  be  said  that  all  these  depressants 
mentioned  influence  the  inotropic  properties  (contractility),  the  bath- 
motropic  (irritability),  and  the  dromotropic  (conductivity  of  stimuli) 
functions  qualitatively  alike,  but  quantitatively  in  different  degrees, 
while  their  effects  on  the  chronotropic  function  (production  of 
stimuli)  follow  special  rules. 

There  can  be  no  doubt  that  there  exist  in  the  heart  special  mechanisms  for 
the  production  of  stimuli,  and  that  these  mechanisms  may  be  affected  by  specific 
pharmacological  actions.  It  makes  no  difference  whether  this  function  is  attrib- 
uted, in  accordance  with  the  neurogenic  hypothesis,  to  nervous  elements  or  to  a 
special  type  of  muscle-cells,  as  demanded  by  the  myogenic  hypothesis.  All  the 
characteristic  functional  properties  of  the  cardiac  muscle  are  found  also  in  the 
apex  of  the  heart,  in  which  under  usual  conditions  the  capacity  for  the  inaugura- 
tion of  stimuli  is  lacking,  and  which,  therefore,  under  normal  conditions  remains 
at  rest  when,  by  clamping,  it  is  physiologically  isolated  from  the  upper  portion 
of  the  heart.  However,  it  contains  a  mechanism  for  the  conduction  of  stimuli, 
for  an  artificial  stimulus  at  any  point  causes  a  simultaneous  contraction  through- 
out its  whole  extent.  It  also  has  a  refractory  period,  and  in  the  apex,  just  as 
in  the  intact  heart,  the  strength  of  the  contraction  is  independent  of  the  intensity 
of  any  stimulus  strong  enough  to  be  effective.  Chloral  hydrate  almost  com- 
pletely abolishes  these  characteristic  functions  of  the  apex,  while  its  suscepti- 
bility to  single  electrical  stimuli  as  well  as  the  function  of  conduction  of  stimuli 
persists,  so  that  the  heart  apex  still  contracts  as  a  whole  after  each  efficient 
minimal  stimulus.  Inasmuch  as  the  power  of  inaugurating  stimuli  is  paralyzed 
throughout  the  whole  heart  simultaneously  with  these  effects  on  the  character- 
istic attributes  of  the  cardiac  function,  the  heart  under  these  conditions  resembles 
in  its  behavior  a  portion  of  intestine  (Magnus)  or  a  Limulus  heart  (Carlson), 
whose  nervous  motor  centres  have  been  anatomically  separated  from  the  muscles. 
In  analogy  with  the  above-mentioned  examples,  there  is  ground  for  concluding 
that  by  the  use  of  chloral  hydrate,  a  drug  that  in  general  paralyzes  nervous 
centres  sooner  than  nerve-fibres  and  muscles,  we  have  succeeded  in  functionally 
eliminating  those  physiological  properties  of  the  heart,  which  are  dependent 
on  nervous  centres  or  ganglia  (Rohde). 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  158,  and  vol.  43,  p.  367. 

Bohme:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  52,  p.  346. 

Brandenburg:   Engelmann's  Arch.,  1903,  Suppl.,  p.  150. 

Braun  u.  Mager:   Wien.  Akad.  Ber.,  1899,  vol.  108,  p.  599. 

Carlson:   Am.  Journal  of  Physiol.,  1904,  vol.  12,  and  1905,  vol.  13. 

Dieballa:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  34,  p.  137,  and  vol.  45,  p.  367. 

Harnack  u.  Witkowski:  Arch.  f.  exp.  Path.  u.  Pharm,  1879,  vol.  11,  p.  1. 

Harnack:  Engelmann's  Arch.,  1904,  p.  415. 


CARDIAC  STIMULANTS  255 

Hedbom:  Skand.  Arch.  f.  Physiol.,  1899,  vol.  9,  p.  1. 

Lowit:   Zeitschr.  f.  Heilk.,  1882,  p.  459. 

Magnus:   Pfliiger's  Arch.,  1904,  vol.  103. 

Rohde:   Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  54,  p.  104. 

Santesson:  Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  vol.  32,  p.  321. 

Tetens,  Hald:   Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  53,  p.  227. 

Weintraud:  Arch.  f.  exp.  Path.,  vol.  34,  p.  37. 

CARDIAC  STIMULANTS 

Stimulation  of  the  motor  mechanism  of  the  heart  is  of  the  greatest 
therapeutic  importance,  for  narcotic  poisons  or  the  toxins  of  infection 
may  and  frequently  do  functionally  depress  the  heart  to  such  an 
extent  that  a  collapse  of  cardiac  origin  develops.  In  such  case  it  is 
important  to  help  the  heart  over  a  temporary  period  of  inefficiency, 
as,  if  under  the  influence  of  a  stimulant  it  beats  better  for  even  a 
short  time,  thus  bringing  about  a  higher  pressure  in  the  aorta,  its  own 
nutrition  is  improved,  and  it  may  thus  be  enabled  to  escape  the  death 
threatened  by  the  poisoning. 

CAMPHOR. — In  the  pathological  disturbances  spoken  of  as  acute 
failure,  camphor  is  the  stimulant  most  used,  although  on  the  normal 
heart  the  favorable  action  of  camphor  cannot  be  demonstrated  with 
certainty.  While  it  is  true  that  a  strengthening  of  the  beats  of  a 
strongly  beating  frog's  heart  may  be  observed  (Heubner,  Baum, 
Maki)  if  the  dose  has,  by  good  fortune,  been  properly  determined, 
often  such  effect  is  not  apparent  (Alexander-Levin).  Moreover,  only 
in  certain  cases  does  camphor  produce  an  improvement  in  function 
in  the  cat's  heart  perfused  according  to  Langendorff's  method  (Selig- 
mann).  On  the  other  hand,  in  pathologically  weakened  hearts  it 
proves  itself  in  incontrovertible  fashion  to  be  a  stimulant  to  the 
automatic  motor  mechanism,  increasing  the  frequency  and  the  power 
of  the  heart-beat. 

It  can  be  especially  well  shown  on  the  frog's  heart  that  camphor 
can  overcome  a  condition  of  standstill.  As  a  result  of  stimulation  of 
the  motor  mechanism,  the  inhibition  is  interrupted  or  the  paralytic 
standstill  resulting  from  narcosis  of  the  motor  centres  is  overcome. 

If  a  heart  which  has  been  stopped  by  muscarine  is  exposed  to  camphor  vapor 
or  to  NaCl  solution  containing  minimal  quantities  (1-1000)  of  this  drug,  more 
or  less  frequent  pulsations  interrupt  the  standstill  (Harnack  u.  Witkowski) , 
while  at  the  same  time  the  persistence  of  the  inhibition  is  evidenced  by  the 
well-marked  diastole  of  the  heart.  Camphor,  being  a  chemical  stimulant  for  the 
.  motor  centres,  is  able  to  overcome  the  inhibition,  just  as  during  a  muscarine 
standstill  each  mechanical  stimulation  excites  a  contraction. 

Camphor  acts  also  as  a  direct  antagonist  to  the  depressant  poisons. 
At  a  time  when,  for  example,  the  chloralized  heart  is  beating  with 
extreme  slowness,  the  application  of  camphor  starts  it  beating  more 
rapidly  and  the  contractions  become  more  powerful. 

Even  some  minutes  after  the  heart  has  ceased  to  beat  camphor  can  start 
it  beating  again  (Bohme).    This  reviving  action  may  be  most  clearly  shown  on  an 
olated  and  perfused  frog's  heart  poisoned  by  chloral,  by  adding  camphor  to  the 


256  PHARMACOLOGY  OF  CIRCULATION 

perfusion  fluid  which  already  contains  chloral.  Although  the  heart  may  already 
be  severely  poisoned  by  chloral  and  continues  to  be  subjected  to  its  action,  after 
camphor  is  added  to  the  perfusion  fluid  the  heart  action  is  at  once  improved  and 
the  frequency  and  strength  of  the  contractions  are  both  increased.  (Fig.  23.) 

Camphor  is  thus  able  to  revive  the  motor  mechanism  of  the  heart 
at  a  time  when  the  automatic  centres  are  threatened  with  extinction. 
As  this  automatic  mechanism  acts  under  ordinary  conditions  with 
maximal  efficiency,  the  favorable  action  of  camphor  cannot  be  well 
observed  on  a  normal  heart. 

The  above-cited  actions  have  been  well  established  for  the  frog's  heart, 
and  it  may  be  considered  as  proved  that  camphor  will  exert  the  same  effect  on 
the  pathologically  disturbed  automatic  centres  in  the  hearts  of  the  higher  species. 
However,  the  experimental  demonstration  of  this  is  much  more  difficult  in  mam- 
mals, for  in  them  it  is  not  so  easy  to  bring  about  a  stationary  condition  of 
disturbed  heart  function  or  to  study  the  actions  of  drugs  thereon. 


•—•——••—<.  After  chloral  has  acted 

Normal  for  20  minute* 

A H A— 

During  perfusion  with  chloral  and  camphor. 
AJUUULJLJt  UAAMAAAMAAWUl 


Two  minutes  later  Ten  minutes  later 

FIG.  23. — Suppression  of  chloral  standstill  by  camphor  in  a  perfused  frog's  heart 

Camphor  possesses  further  a  distinct  action  in  cases  of  a  peculiar 
disturbance  of  the  heart  functions  known  as  fibrillation.  By  this  term 
is  understood  the  violent  but  fully  uncoordinated  contractions  of  the 
whole  reticulum  of  the  cardiac  muscles,  a  condition  which  may  be 
induced  in  the  living  heart  by  sudden  interruption  of  the  coronary 
circulation,  as  also  by  acute  poisoning  with  chloroform  and  other 
toxic  substances.  Fibrillation  may  also  be  readily  induced  in  the  sur- 
viving heart  by  direct  stimulation  with  the  induced  current,  such 
stimulation  causing  the  surviving  cat's  heart  to  fibrillate  either  per- 
sistently or  for  some  time.  If,  however,  to  the  usual  perfusion  fluid 
small  amounts  of  camphor  be  added  and  the  perfusion  be  continued, 
the  fibrillation  ceases,  and  renewed  stimulation  with  the  induction 
current  causes  only  momentary  fibrillation  (Seligmann,  Gottlieb, 
Klemperer,  opposed  by  Winterberg). 

Suppression  of  the  fibrillation  may  account  for  the  therapeutic 
effect  of  camphor  in  cases  where  the  auricle  alone  is  affected.  Fibril- 
lation of  the  ventricle  must  quickly  cause  death,  on  account  of  the 


CARDIAC  STIMULANTS  257 

interruption  of  the  circulation  resulting  from  it.  On  the  other  hand, 
in  man  cases  are  observed  with  very  rapid  and  irregular  pulse,  present- 
ing a  clinical  picture  which  Cushny  and  Edmunds  have  shown  to  re- 
semble closely  the  phenomena  observed  in  dogs  when  fibrillation  of  the 
auricles  alone  has  been  induced.  In  such  cases,  as  soon  as  the  auricle 
begins  to  beat  regularly  again,  the  ventricular  pulse  also  becomes 
normal.  The  heart  action  during  the  death  struggle,  which  is  often 
improved  by  camphor,  presents  certain  analogies  with  this  condition. 

From  the  above  it  is  clear  why  the  normal  blood-pressure  will  not 
be  raised  by  any  action  of  camphor  on  the  heart,  although  it  is  raised 
by  doses  which  cause  convulsions,  this  being  due  to  stimulation  of 
the  vasomotor  centres.  Only  when  the  circulation  is  depressed  may 
a  rise  in  blood-pressure  result  from  doses  not  large  enough  to  cause 
convulsions.  The  role  played  here  by  an  improvement  of  the  vessel 
innervation  will  be  discussed  later.  There  is  no  doubt  that  when 
camphor  is  used  to  revive  the  circulation  in  dying  patients,  in  whom 
the  automatic  centres  in  the  heart  are  failing,  it  may  exert  a  direct 
favorable  action  on  the  heart* 

Musk  was  formerly  much  used  for  the  same  indications  as  camphor, 
but  to-day  it  is  used  but  seldom  and  is  no  longer  officinal.  There 
are  no  experimental  investigations  which  would  justify  its  use 
clinically. 

BIBLIOGRAPHY 

Alexander-Levin :  Arch,  f .  exp.  Path.  u.  Pharm.,  1890.  vol.  27,  p.  226. 

Baum:  Zbl.  f.  d.  med.  Wiss.,  1870,  vol.  8. 

Bernstein:  Engelmann's  Arch.,  1906,  Suppl.,  p.  343. 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  158. 

Bohme,  A. :  Arch.  £.  exp.  Path.  u.  Pharm.,  1905,  vol.  52,  p.  346. 

Carlson:  Am.  Journ.  of  Physiol.,  1906,  vol.  17. 

Cushny  and  Edmunds:  Am.  Journal  of  the  Medical  Sciences,  1907,  new  series, 

vol.  133,  p.  66. 

Gottlieb:  Ztschr.  f.  exp.  Path.  u.  Ther.,  1905,  vol.  2,  p.  385,  and  1906,  vol.  3,  p.  588. 
Hamalinen,  J.:  Skand.  Arch.  f.  Physiol.,  1908,  vol.  21,  p.  64. 
Harnack  u.  Witkowski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  5,  p.  401. 
Heubner:  Arch.  f.  Heilk..  1870,  vol.  9. 

Klemperer :  Ztschr,  f .  exp.  Path.  u.  Ther.,  1907,  vol.  4,  p.  389. 
Maki:  Diss.,  Strassburg,  1884. 

Seligmann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  52,  p.  333. 
Winterberg:  Pfluger's  Arch.,  1903,  vol.  94,  p.  455. 
Winterberg:     Ztschr.  f.  exp.  Path.  u.  Ther.,  1906,  vol.  3,  p.  182. 

ETHER. — The  subcutaneous  injection  of  ether  is  often  employed 
as  a  cardiac  analeptic  (restorative),  although  it  has  not  been  possible 
to  demonstrate  that  ether  possesses  a  direct  stimulating  effect  on  the 
heart's  activity.  Although  in  conditions  of  collapse  temporary  im- 
provement of  the  circulation  may  follow  the  subcutaneous  injection 
of  ether,  this  is,  in  part  at  least,  to  be  attributed  to  the  sensory  stimu- 
lation caused  by  the  powerful  and,  in  conscious  patients,  very  painful 

*  [Recently  Heard  (Am.  J.  of  Med.  Sci.,  1931,  vol.  135,  p.  238)  in  a  carefully 
nducted  clinical  investigation  has  failed  to  note  any  favorable  effects  on  the 
iulation  following  the  administration  of  camphor. — TK.] 

17 


258  PHARMACOLOGY  OF  CIRCULATION 

irritation  of  the  tissues  which,  the  injection  causes.  Its  reflex  effects 
on  the  respiration  and  circulation  must,  therefore,  be  considered  as 
similar  to  those  arising  from  other  sensory  stimuli.  They  may,  in 
combination  with  the  vasomotor  effect  of  ether,  contribute  to  the  im- 
provement of  the  blood-pressure  and  thus  to  a  better  flow  of  blood 
through  the  heart. 

In  ether  narcosis  the  frequency  of  the  pulse  is  regularly  increased, 
in  adults  often  to  above  100,  in  children  even  more  so.  In  experi- 
ments on  animals  also,  the  pulse  frequency  is  regularly  increased 
by  the  inhalation  of  not  too  concentrated  ether  vapor  (Elf strand). 
an  effect  quite  contrary  to  that  caused  by  chloroform.  This,  however, 
is  not  to  be  attributed  to  a  direct  effect  on  the  heart,  for  this  accelera- 
tion does  not  occur  if  the  heart  be  isolated  from  the  central  nervous 
system  (Bock).  It  is,  therefore,  of  central  origin,  as  the  result  of  either 
direct  or  reflex  actions  on  the  centres  of  the  extracardial  nerves.  This 
acceleration  of  the  pulse  must  aid  in  producing  the  rise  in  blood- 
pressure  observed  at  the  commencement  of  narcosis.  The  action  of 
ether  on  the  heart  may,  therefore,  be  interpreted  only  as  an  indirect 
one,  for  up  to  the  present  time  there  exists  no  proof  that  it  possesses 
a  direct  favorable  action. 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  158. 
Elfstrand:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  43,  p.  435. 

ALCOHOL. — It  is  a  still  much-discussed  question  whether  alcohol 
exerts  a  direct  stimulating  action  on  the  heart.  Even  the  behavior 
of  the  pulse  has  been  differently  determined  and  interpreted  by  dif- 
ferent observers.  As  a  rule,  in  man  alcohol  accelerates  the  pulse 
(John),  but  in  carefully  conducted  experiments  this  has  at  times 
not  been  the  case  (Zimmerberg,  Wendelstadt).  There  is  no  doubt 
that  the  acceleration  of  the  pulse,  when  it  does  occur,  is,  at  least  in 
part,  due  to  secondary  effects  of  the  action  of  alcohol  on  the  mind, 
as  well  as  to  reflexes  caused  by  its  smell  and  taste  or  by  its  local 
action  on  the  gastric  mucous  membrane.  Recently  Dixon  observed 
that  acceleration  of  the  pulse  did  not  occur  after  absorption  of  alcohol 
from  the  stomach  if  it  were  introduced  highly  diluted,  and  that,  when 
20  per  cent,  alcohol  was  held  in  the  mouth  for  only  a  short  time  and 
then  spit  out,  this  acceleration  passed  off  more  quickly  than  when 
the  alcohol  was  swallowed.  In  experiments  on  animals,  secondary 
effects  resulting  from  actions  on  the  central  nervous  system  are 
apparent  even  after  intravenous  injection.  For  these  reasons,  only 
experiments  on  the  isolated  organ  are  suitable  for  the  determination  of 
the  extent  to  which  a  direct  stimulant  action  on  the  motor  mechanism 
of  the  heart  is  responsible  for  the  acceleration  of  the  pulse.  The  same 
holds  good  for  the  effects  on  the  strength  of  the  contractions. 


ALCOHOL  AND  THE  HEART  259 

Experiments  on  the  isolated  heart  indicate  that,  beginning  with  a 
concentration  of  about  1  per  cent.,  alcohol  exerts  a  distinctly  harmful 
influence  on  the  cardiac  function  (Loeb}.  According  to  many 
authors  who  have  subjected  the  isolated  frog  (Dreser,  Dieballa)  or 
mammalian  heart  (Bock,  Tunnicliffe  and  Rosenheim,  Kochmann)  to 
the  influence  of  even  weaker  solutions,  only  a  depressant  action  is 
exerted,  and  all  favorable  action  is  denied.  On  the  other  hand,  Loeb, 
using  even  smaller  amounts  of  alcohol,  observed  a  distinct  although 
slight  stimulant  action  on  the  surviving  cat's  heart  perfused  according 
to  Langendorff.  This  favorable  effect  was  obtained  by  the  use  of 
from  0.13-0.3  per  cent,  alcohol,  and  was  especially  marked  in  such 
hearts  as  were  previously  beating  poorly.  A  favorable  influence  was 
also  obtained  as  an  after  effect  of  stronger  concentrations  after  the 
alcohol-containing  blood  had  been  washed  out.  Wood  and  Hoyt  pro- 
duced an  unmistakable  increase  of  the  pulse  volume  of  the  frog's 
heart  by  adding  0.25-0.5  per  cent,  alcohol,  and  Dold  obtained  similar 
results.  Nevertheless,  the  differences  observed  in  the  mammalian 
experiments  were  only  slight  ones  and  the  results  were  by  no  means 
constant.  This  seems  to  indicate  that  the  normal  heart  working  under 
favorable  conditions  is  but  slightly  influenced  by  small  amounts  of 
alcohol  (just  as  we  saw  similar  conditions  obtaining  for  the  action  of 
camphor),  and  that  only  the  feeble  contractions  observed  during 
depressed  cardiac  activity  are  favorably  influenced  by  suitable  doses 
of  alcohol.  This  is  evident  from  Dixon's  experiments.  In  these  ex- 
periments, conducted  on  mammalian  hearts  perfused  with  Ringer's 
solution,  with  or  without  the  addition  of  dextrose,  the  strength  of  the 
contractions  was  usually  increased  when  the  fluid  contained  0.05-0.3 
per  cent,  of  alcohol.  This  positive  effect  was,  however,  much  more  pro- 
nounced in  hearts  which  had  previously  been  kept  beating  for  hours 
without  any  addition  of  organic  nutrient  material  to  the  perfusion 
fluid,  while  this  effect  was  either  much  slighter  or  was  entirely  lacking 
in  hearts  which  were  beating  strongly  and  which  had  been  kept  well 
nourished  through  the  addition  of  glucose  to  the  perfusion  fluid. 
Stronger  concentrations  of  alcohol  strengthened  the  heart's  action 
only  temporarily,  and  quickly  produced  harmful  results. 

Some  grounds  for  the  belief  that  alcohol  serves  the  heart  as  a 
nutrient  material  are  found  in  the  fact  that  the  alcohol  produces  a 
mch  more  pronounced  stimulation  in  badly  nourished  hearts  than 
hearts  which  had  been  kept  beating  in  a  nutrient  solution  containing 
glucose  but  no  alcohol.     This  drug  easily  passes  into  all  tissues,  and 
le  experiments  of  Dixon  make  it  probable  that  it  may  be  used  as 
source  of  energy.    In  fact,  a  part  of  the  alcohol  added  to  the  per- 
sion  fluid  is  consumed   (Hamili).     Moreover,  according  to  Dixon, 
glucose  improves  the  action  of  the  heart  quite  similarly  to  alcohol, 
id  is  also  consumed  when  perfused  through  the  active  mammalian 
leart  (Johannes  Muller,  Locke  and  Rosenheim). 


260  PHARMACOLOGY  OF  CIRCULATION 

BIBLIOGRAPHY 

Bock,  A.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  173,  here  literature. 

Dieballa:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  34,  p.  137. 

Dixon:  Journ.  of  Physiol.,  vol.  35. 

Dold:  Inaug.  Diss.,  Tubingen,  1906. 

Drescr:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  24,  p.  236. 

Hamill:  Journ.  of  Physiol.,  1910,  vol.  39,  p.  476. 

John :  Ztschr.  f.  exp.  Path.  u.  Ther.,  1909,  vol.  5. 

Kochmann:  Arch,  de  Pharmacodyn.  et  de  Ther.,  1904,  vol.  13,  p.  329. 

Locke  and  Rosenheim:  Journ.  of  Physiol.,  1904,  vol.  31. 

Loeb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  52,  p.  459. 

Mailer,  Johannes:  Ztschr.  f.  allg.  Physiol.,  1904,  vol.  3. 

Tunnicliffe  and  Rosenheim:  Journ.  of  Physiol.,  1903,  vol.  29. 

Wendelstadt:  Pfliiger's  Arch.,  1899,  vol.  76,  p.  233. 

Wood  and  Hoyt:  Memoirs  of  National  Acad.  of  Sciences,  1905,  p.  10. 

Zimmerberg:  Inaug.  Diss.,  Dorpat,  1869. 

Epinephrin  is  a  typical  stimulant  to  the  heart's  activity. 

The  stimulation  of  the  accelerator  nerve-endings  manifests  itself 
especially  in  the  surviving  mammalian  heart  by  acceleration  of  the 
heart  rate  and  by  a  striking  increase  in  the  strength  of  the  contractions. 
This  effect,  in  contradistinction  to  that  of  camphor,  also  occurs  on 
hearts  which  are  beating  well  and  are  well  nourished. 


Epinephrin 


FIG.  24. — Effect  of  epinephrin  on  the  isolated  cat's  heart. 

Through  its  specific  power  of  stimulating  the  vasomotor  nerve- 
endings  in  the  vessel  walls,  epinephrin,  when  injected  intravenously, 
causes  a  general  vasoconstriction  and  an  enormous  rise  in  blood- 
pressure.  Such  an  increased  resistance  in  the  vessels  lays  upon  the 
heart  a  great  burden  while  it  is  emptying  itself.  Because  of  this 
preponderance  of  the  action  upon  the  vessels,  it  may  happen  that 
the  heart  breaks  down  as  a  result  of  the  rise  in  blood-pressure,  but, 
when  epinephrin  is  injected  into  a  depressed  circulation,  the  blood- 
pressure  need  not  rise  above  the  normal,  and  then  the  increased  power 
of  the  heart's  contractions  is  clearly  apparent. 

That  this  is  not  the  result  simply  of  the  indirect  effect  of  improved 
blood  flow  in  the  heart,  but  that  it  is  due  to  a  direct  action  on  the 
heart,  is  shown  by  experiments  in  which  the  heart  has  first  been 
brought  to  a  standstill  by  chloral  hydrate,  chloroform,  or  potassium 
salts,  or  else  has  been  so  depressed  that  it  is  beating  very  feebly  and 
infrequently.  If  then  epinephrin  be  injected  into  the  veins  and  reaches 
the  heart,  the  heart  revives  again  and  beats  more  frequently  and  more 
powerfully  than  at  the  start. 

As  the  epinephrin  is  distributed  around  in  the  circulation  by 
the  restored  activity  of  the  heart  and  is  thus  able  to  act  on  the  vessels, 


EPINEPHRIN  AND  THE  HEART  261 

the  blood-pressure  rises  again  very  markedly,  even  if  it  had  previously 
sunk  to  the  zero  point.  This  reviving  action  of  epinephrin  is,  however, 
very  fleeting,  because  this  drug  is  very  unstable  when  injected  into 
the  circulation.  However,  the  favorable  results  may  outlast  its  fleet- 
ing action  in  case  the  cause  of  the  fall  in  pressure — for  example, 
chloroform  or  potassium  salts — has  in  the  meantime  been  eliminated. 
In  animal  experiments,  in  cases  of  apparent  death  caused  by  chloro- 
form, it  is  possible  by  the  use  of  epinephrin  to  start  the  heart  beating 
again.* 

This  cardiac  action  of  epinephrin  may  be  demonstrated  in  the 
isolated  "heart-lung"  circulation.  With  the  heart  under  these  con- 
ditions beating  independently  of  all  influences  from  the  central  ner- 
vous system,  the  frequency  of  the  pulse  increases  simultaneously  with 
the  strengthening  of  the  contractions.  On  the  other  hand,  in  the 
intact  circulation  the  pulse  is  at  first  slow,  for  the  rise  in  blood- 
pressure  causes  a  central  vagus  stimulation,  which  overcomes  the 


Injection 


Flo.  25. — Effect  of  the  injection  of  suprarenal  extract  1  minute  and  35 
seconds  after  cessation  of  heart-beat. 

tendency  of  the  heart  to  contract  more  rapidly  as  a  result  of  the 
direct  action  on  the  heart.  Only  later  does  the  excitation  of  the  motor 
mechanism  of  the  heart  gain  the  upper  hand  so  that  the  heart  may 

beat  more  rapidly. 

BIBLIOGRAPHY 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  99,  and  1899,  vol.  43, 

p.  286. 
Oliver  and  Schafer:  Journ.  of  Physiol.,  1895,  vol.  18. 

THE  ACTION  OF  DIGITALIS  ON  THE  HEART 

The  members  of  the  pharmacological  groups  of  digitalis  and  caf- 
feine are  also  cardiac  stimulants,  influencing  the  contractions  of  the 
heart  in  characteristic  and,  for  each  group,  different  fashion. 

The  active  principles  of  the  digitalis  leaves  and  a  number  of  other 
glucosides  occurring  in  very  different  species  of  plants,  all  produce 
a  similar  typical  effect  on  the  activity  of  the  heart.  Digitalin  and 
digitoxin,  derived  from  the  digitalis  leaves,  and  strophanthin,  derived 
from  strophanthus  seeds,  are  the  most  important  members  of  this 
group.  Their  typical  action  is  characterized  by  an  especially  elective 
action  on  the  heart,  which  is  well  shown  during  the  development  of  the 

*  [Also  in  human  beings,  particularly   if  the  action  of  the  epinephrin  be 
ipplemented  by  massage  of  the  heart. — TB.] 


262 

digitalis  action  on  the  heart  of  a  frog.  At  a  time  when  this  organ, 
having  passed  through  all  phases  of  the  poisoning,  has  been  brought 
to  a  complete  standstill,  the  frog  shows  no  symptoms  of  toxic  action 
on  his  nervous  system,  and,  inasmuch  as  the  nervous  system  of  cold- 
blooded animals  preserves  its  excitability  for  a  considerable  period 
after  cessation  of  the  blood  flow,  the  frog  is  still  able  to  hop  around 
quite  normally. 

In  the  following  discussion  the  substances  belonging  to  the  pharma- 
cological group  of  digitalis  will  be  spoken  of,  for  the  sake  of  brevity, 
as  digitalis  bodies,  or  substances,  although  typical  members  of  this 
group  occur  in  other  plants. 

ACTION  ON  THE  FROG'S  HEART. — If  a  full  dose  of  a  digitalis  body 
be  injected  into  a  Rana  temporaria,  the  following  phenomena  may  be 
observed  on  the  exposed  heart  (Bohm}.  After  some  minutes  the 
relaxation  appears  to  be  increased,  and  to  last  somewhat  longer  than 
normally.  The  frequency  of  the  beats  is  slightly  diminished,  while 
the  contraction  is  more  energetic, — that  is,  the  ventricle  at  the 
height  of  its  contraction  is  paler  than  it  was  before  administration  of 
the  drug,  as  it  drives  out  its  contents  more  completely.  Then  there 
occur  occasional  temporary  diastolic  pauses,  and  later  the  movements 
of  the  heart  become  strikingly  irregular,  owing  to  the  fact  that  all 
portions  of  the  ventricle  are  no  longer  equally  relaxed  in  each  diastole. 
As  these  partial  diastoles  of  the  different  parts  of  the  ventricle  do 
not  occur  with  any  regularity,  the  blood  is  shoved  hither  and  thither 
in  the  heart,  and  the  peculiar  picture  of  ' '  heart  peristalsis ' '  develops. 
This  phase,  which  is  often  interrupted  by  a  series  of  regular  heart- 
beats, is  succeeded  sooner  or  later  by  a  persistent  contraction  of  the 
ventricle  (systolic  standstill),  which  represents  the  characteristic  final 
stage  of  the  pharmacological  action.  The  ventricle  remains  completely 
contracted  and  emptied  of  blood,  while  the  auricle,  distended  with 
blood  to  bursting,  continues  to  beat  for  some  time,  finally  passing 
into  a  condition  of  stoppage  in  diastole.  Even  after  the  heart  has 
passed  into  the  phase  of  systolic  standstill,  it  has  by  no  means  lost 
its  power  of  beating,  but  the  tendency  of  the  ventricle  to  remain  in  a 
contracted  condition  prevents  its  relaxation.  If  at  this  stage  relaxa- 
tion is  artificially  brought  about  through  hydrostatic  pressure,  this 
forced  diastole  is  followed  by  a  series  of  active  heart-beats  (Schmiede- 
~berg}.  This  standstill  is,  therefore,  at  the  beginning  to  be  con- 
sidered as  due  to  a  persistent  stimulation  of  the  contracting  mechan- 
ism and  not  as  due  to  a  paralysis.  However,  the  cardiac  muscle  finally 
becomes  unexcitable  and  dies  in  a  state  of  contraction. 

A  closer  analysis  of  the  characteristic  course  of  this  poisoning  is 
especially  interesting,  for  these  first  actions  on  the  frog's  heart 
exhibit  features  of  that  digitalis  action  which  is  of  importance  in  its 
therapeutic  application.  Such  closer  analysis  is  possible  only  on  the 
isolated  heart,  for  the  heart  acting  in  conjunction  with  the  whole 


DIGITALIS  AND  THE  HEART  263 

circulation  is  influenced  by  secondary  factors, — for  example,  by  the 
changing  inflow  of  blood  from  the  vessels. 

It,  therefore,  was  significant  of  a  decisive  advance  in  our  knowl- 
edge of  digitalis  when  Bohm,  in  1872,  and,  later  and  more  completely, 
Williams  investigated  the  actions  of  the  digitalis  bodies  on  the  frog's 
heart  beating  in  an  artificial  circulation.  It  was  shown  by  this  author 
that  the  diastolic  relaxation  was  increased  quite  independently  of  any 
retardation  of  the  rate,  the  ventricle  relaxing  to  a  greater  extent 
under  an  unchanged  diastolic  pressure,  while  the  systolic  contractions 
pump  out  this  greater  content  very  completely.  The  pulse  volume  of 
the  heart,  therefore,  increases,  as  does  the  pulse  pressure  in  the  arti- 
ficial circulation,  and  thus  the  ''heart  work"  accomplished  by  each 
contraction  is  increased,  as  is  also  the  work  done  per  minute,  unless 
the  rate  of  the  heart-beats  is  too  greatly  diminished. 


AA/WWW 


Normal  10  min.  after  helleborein  10  minutes  later  15  min.  later.   Standstill 

FIQ.  26. — Tracing  from  frog's  heart  (Williams). 

In  this  first  phase  the  digitalis  bodies  produce  two  effects  on  the 
cardiac  function  by  a  "systolic"  and  a  "diastolic"  action.  The 
"diastolic"  action  expresses  itself  in  the  retardation  of  the  heart's 
action  and  in  the  increase  of  the  relaxation.  The  "systolic"  action 
has  its  expression  in  the  more  complete  and  energetic  pumping  out 
of  the  ventricular  contents.  The  heart  under  the  influence  of  digitalis 
works  like  a  pump,  the  piston  of  which  at  each  stroke  is  raised  higher 
and  pushed  in  again  more  completely.  The  absolute  power  of  the 
heart,  however,  is  unchanged, — that  is,  the  piston  of  the  pump  is 
not  more  forcibly  moved  nor  is  it  able  to  overcome  any  higher 
pressure  than  before.  The  heart  does  not  gain  in  muscular  power, 
but  simply  utilizes  its  power  more  efficiently. 

The  slowing  of  the  frog's  heart  which  is  caused  by  digitalis  occurs  quite 
independently  of  the  vagus  centre  and  of  any  action  on  the  vagus  nerve-endings. 
While  previous  atropinization  produces  no  effect,  still  the  "  diastolic  "  digitalis 
action  resembles  to  a  marked  degree  the  vagus  inhibitory  action,  and  actually 
finally  causes  a  lasting  diastolic  standstill  of  the  frog  heart  beating  in  connec- 
tion with  the  frog- heart  manometer,  if  the  digitalis  bodies  have  been  added  to  the 
nutrient  fluid  in  quantities  distinctly  smaller  than  those  which,  under  like 
conditions,  cause  the  systolic  standstill  ( Werschinin ) .  This  standstill  in  diastole 
occurring  after  very  small  doses  of  digitalis  is  the  maximal  expression  of  the 
"diastolic"  action  of  digitalis,  while  the  systolic  standstill  is  that  of  the 
"  systolic  "  action.  In  the  frog  under  the  conditions  of  the  normal  circulation, 
the  "  systolic "  action  always  gains  the  upper  hand  when  the  dose  is  large 
enough  to  produce  any  effects.  However,  during  the  gradual  absorption  of  small 
doses  one  may  observe,  in  the  intact  frog  or  with  a  Williams  apparatus,  a 
contest  between  the  two  actions,  during  which  fairly  long  diastolic  pauses  occur 
before  the  systolic  stoppage  takes  place. 


264 


PHARMACOLOGY  OF  CIRCULATION 


The  "diastolic"  digitalis  action — slowing  of  the  heart  rate  and  in- 
crease of  the  relaxation — resembles  an  inhibitory  action,  and  the 
strengthening  of  the  contractions  reminds  one  of  a  stimulating  action 
on  the  accelerator  nerves,  but  they  both  occur  quite  independently  of 
the  extracardial  nerves.  It  is  not  possible  at  the  present  time  to 
determine  which  of  the  elements  in  the  heart  are  acted  on  by  the 
digitalis  bodies. 

THE  ACTION  ON  THE  ISOLATED  MAMMALIAN  HEART  is  fundamentally 
similar  to  that  on  the  frog's  heart,  except  that  in  the  mammalian 
heart  the  "diastolic"  digitalis  action  is  overshadowed  by  the  systolic 
(Hedbom).  The  slowing  of  the  pulse,  which  in  man  is  well  marked 
after  medicinal  doses,  as  also  in  the  early  stages  of  poisoning  in  the 
higher  animals,  is  not  caused  peripherally,  as  is  the  case  in  the  frog's 
heart,  but  is,  at  least  in  the  case  of  most  of  the  pure  principles  thus 
far  investigated,  entirely  the  result  of  stimulation  of  the  vagus  centre. 
It  therefore  does  not  occur  after  section  of  the  vagi,  or  after  destruc- 
tion of  the  central  nervous  system,  or  after  atropine  (Ackermann, 
Kochmann) . 


Before  digitoxin  After  digitozin 

Fia.  27. — Curves  obtained  from  a  surviving  cat's  heart. 

That  "diastolic"  action  of  digitalis  which  occurs  independently 
of  the  vagus  is  only  faintly  indicated  in  the  mammalian  heart  under 
the  influence  of  this  drug,  although  a  more  pronounced  relaxation  in 
diastole  has  been  observed  in  the  cat's  heart  when  perfused  with 
digitalis  according  to  Langendorff 's  method.  On  the  contrary,  the 
pulse  frequency  of  the  mammalian  heart  is  markedly  increased  when 
it  is  isolated  and  rendered  independent  of  the  central  nervous  system 
and  subjected  to  the  influence  of  digitalis.  It  may  be  that  this  pre- 
ponderance of  the  accelerator  action  is  responsible  for  the  fact  that 
the  ''diastolic"  action  of  digitalis,  which  is  so  well  developed  in  the 
frog's  heart,  is  barely  indicated  in  the  mammal. 

In  the  isolated  mammalian  heart  the  "systolic"  digitalis  action 
causes  a  more  complete  contraction,  in  which  evidently  both  ventricles 
are  involved  (Brawn  u.  Mayer}.  The  effect  of  the  more  complete 
systole  on  the  blood-pressure  and  on  the  pulse  volume  of  the  heart 
can  be  measured  by  inserting  into  the  empty  ventricle  a  balloon  which 
just  fills  its  cavity  and  which  measures  the  changes  in  its  pressure 
and  volume.  Under  the  influence  of  the  digitalis  bodies  the  work  done 


DIGITALIS  AND  THE  HEART  265 

by  a  single  contraction  of  the  heart  can  be  augmented  2y2  to  3  times 
(Gottlieb  u.  Magnus). 

As  the  poisoning  develops  these  early  effects  are  followed,  just 
as  is  the  case  with  the  frog's  heart,  by  irregularity  of  the  heart  action, 
and  finally,  as  the  heart  relaxes  less  and  less,  the  heart  stops  in  a  state 
of  maximal  contraction.  This  systolic  standstill  of  the  mammalian 
heart  may  also  at  first  be  removed  by  forcible  dilatation  of  the  con- 
tracted muscle-fibres. 

The  fact  that  the  heart,  beating  in  the  intact  circulation,  finally  stops  in 
diastole  instead  of  in  systole  is  not  due  to  a  qualitative  difference  in  the  end 
stages  of  the  toxic  action  in  cold-  and  warm-blooded  animals,  but  to  the  greater 
susceptibility  of  the  mammalian  heart  to  an  interruption  of  its  coronary  circu- 
lation, the  harmful  effect  of  even  moderate  diminution  of  the  diastolic  relaxation 
so  interfering  with  the  blood  supply  of  the  heart  muscles  that,  unless  the  heart 
be  artificially  perfused,  the  further  development  of  the  augmentation  of  the 
systolic  contraction  is  interrupted. 

Strophanthin  blood 

£.  Systolic  standstill 


Flo.  28.— 1.  Increase  in  the  variations  of  the  intraventricular  pressure  after  Strophanthin. 
2.  Their  progressive  diminution  until  finally  the  heart  stops  in  systole. 

Another  fundamental  action  of  digitalis,  that  of  regulating  a 
previously  irregular  cardiac  action,  is  well  brought  out  on  the  isolated 
mammalian  heart.  Even  after  small  dosage  this  action  is  clearly 
developed  and  is  therapeutically  of  great  significance,  but  thus  far  this 
action  is  not  susceptible  of  a  closer  analysis  (see  p.  266). 

It  may  readily  be  understood  that  the  improvement  of  the  cardiac 
function  by  digitalis  will  be  materially  dependent  on  the  character 
of  contractions  at  the  time  when  the  drug  is  used.     If  before  its 
administration  the  systolic  contraction  is  already  a  nearly  optimal 
one,  the  augmentation  of  the  heart's  performance  will  not  be  so  great 
as  it  would  be  in  case  the  contractions  were  feeble.    This  action  may, 
therefore,  be  better  demonstrated  on  a  Langendorff's  heart  prepara- 
tion which  is  relatively  poorly  supplied  with  blood,  and  which  is 
sating  relatively  weakly,  than  on  a  fully  normal  organ,  which  is 
lormally  contracting  nearly  to  its  full  extent  in  the  circulation  of  a 
jalthy    animal  (Magnus   u.    Sowton).    Bock,   in   his    experiments 
dth  the   "heart-lung"  circulation,   found  that  the  rise  in  blood- 
>ressure  resulting  from  an  increase  of  the  pulse  volume  of  the  heart 
ras  especially  striking  in  hearts  which  had  been  beating  inefficiently. 
An  augmentation  of  the  pulse  volume  of  the  heart  beating  in  the 
itact  circulation  must,  under  otherwise  equal  conditions,  cause  an 
icrease  of  the  aortic  blood-pressure.     In  accord  with  this  the  mean 


266  PHARMACOLOGY  OF  CIRCULATION 

pressure  in  the  Williams  frog-heart  apparatus  is  increased  by  the 
digitalis  bodies  (see  curve,  Fig.  26,  p.  263). 

On  the  other  hand,  the  pressure  in  the  pulmonary  arteries  is  not 
increased,  or  at  least  is  much  less  increased  than  the  pressure  in  the 
aorta.  This  difference  is  not  due  to  a  different  action  on  the  two 
ventricles,  but  to  the  fact  that  the  pulmonary  vessels  are  more  readily 
distended  and  may  be  more  easily  filled  without  increasing  the  resist- 
ance in  them  (Wood,  Openchowski,  Mellin,  Plumier). 

The  volume  changes  of  the  ventricle  may  be  measured  in  the 
living  animal  by  means  of  the  plethysmograph  or  similar  instruments 
(Cushny),  a  diminution  of  the  heart  volume  in  systole  justifying 
the  conclusion  that  its  contents  are  more  completely  expelled.  The 
total  amount  of  work  done  by  the  heart  beating  in  the  intact  circu- 
lation depends,  however,  not  alone  on  the  pulse  volume  of  the  single 
heart-beats  but  on  the  pulse  frequency.  In  the  therapeutically  im- 
portant stage  of  their  action,  the  stimulation  of  the  vagus  centre 
l)y  the  digitalis  bodies  may  so  diminish  the  number  of  heart-beats 
that  the  minute  volume  of  blood  pumped  out  by  the  heart  is,  as  a 
result  of  this  slowing,  increased  only  moderately,  or  may  in  fact 
be  actually  diminished. 

After  toxic  doses  of  digitalis  a  sudden  change  in  the  rate  of  the 
pulse,  from  retardation  to  acceleration,  may  occur.  This  is  due  to  a 
peripheral  vagus  depression  or,  more  correctly  expressed,  to  an  over- 
excitability  of  the  heart  that  renders  it  less  susceptible  to  vagus  inhibi- 
tion. With  large  enough  doses  there  finally  develops  irregularity  of 
the  heart  action,  and  usually  the  heart  stops  very  suddenly  in  diastole 
•or  in  systole  (see  above). 

[To-day  no  discussion  of  the  action  of  digitalis  on  the  heart  is  com- 
plete unless  it  includes  at  least  a  brief  consideration  of  its  effects  on 
the  functions  of  conductivity  and  irritability  or  excitability  (see 
p.  244) .  Largely  through  the  admirable  work  'of  Mackenzie,  augmented 
by  the  observations  of  Cushny,  Lewis,  and  others,  it  appears  to  be 
established  that  in  laboratory  animals  and  in  man  under  clinical 
conditions,  digitalis  and  its  congeners  produce  a  distinct  retarding 
effect  on  the  conductivity  of  the  Bundle  of  His,  varying  from  a  slight 
retardation  to  a  complete  blocking.  As  especially  pointed  out  and 
emphasized  by  Mackenzie,  this  complete  or  partial  blocking  effect  of 
digitalis  may  be  of  decisive  importance  for  the  therapeutic  effect  pro- 
duced, resulting  at  times  to  the  advantage  and  at  others  to  the 
disadvantage  of  the  patient.  Clinical  observations,  combined  with 
subsequent  post-mortem  examination,  have  demonstrated  that  certain 
pathological  changes  in  this  Bundle  of  His  favor  the  development 
of  this  blocking  effect. 

In  this  connection  it  appears  well  to  emphasize  the  clinical  impor- 
tance of  the  action  of  digitalis  in  exciting  or  rendering  more  irritable 
the  motor  ganglia  or  centres  in  the  heart,  for  it  has  been  established 


CAFFEINE  AND  THE  HEART  267 

clinically  that  under  the  influence  of  digitalis  the  tendency  to  pre- 
mature contractions  or  extra  systoles  may  be  decidedly  aggravated. 
It  should,  however,  be  stated  at  the  same  time  that,  by  its  other  actions 
on  the  whole  circulatory  system,  the  administration  of  digitalis  may 
bring  about  a  generally  improved  circulation,  although  increasing  the 
tendency  to  extra  systoles,  or  at  times  causing  them  to  diminish  in 
frequency  or  disappear  at  least  for  an  indefinite  period. — TR.] 

BIBLIOGRAPHY 

Ackermann:  Deut.  Arch.  f.  klin.  Med.,  1873,  vol.  11. 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41. 

Bohm:   Pfliiger's  Arch.,  1872,  vol.  5. 

Braun  u.  Mayer:   Sitzungsber.  d.  Akad.  d.  Wiss.,  Wien,  1899,  vol.  108. 

Oushny:  Am.  Journ.  of  Exper.  Med.,  1897,  vol.  2. 

Gottlieb  u.  Magnus:   Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  51. 

Hedbom:   Skand.  Arch.  f.  Physiol.,  1898,  vol.  8. 

Kochmann:   Arch,  de  Pharmacodyn.  et  de  Therapie,  1905,  vol.  16. 

Lhotak:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  58. 

Magnus  u.  Sowton:   Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  255. 

Mellin:   Skand.  Arch.  f.  Physiol.,  1904,  p.  149. 

Openchowski:   Ztschr.  f.  klin.  Med.,  1887,  vol.  16. 

Plumier:  Journal  de  Physiologic  et  Pathologie  generate,  1905,  vol.  7. 

Schmiedeberg:   Beitr.  zur  Physiologie,  Leipzig,  1875. 

Werschinin:   Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 

Williams:  Arch.  f.  exp.  Path.  u.  Pharm.,  1880,  vol.  13. 

Wood:  Am.  Journ.  of  Physiol.,  1902,  vol.  6. 

CAFFEINE. — To  the  discussion  of  the  pharmacology  of  the  digitalis 
group  succeeds  that  of  caffeine,  which  is  often  considered  by  clinicians 
to  resemble  digitalis.  Its  chief  action  on  the  circulation  is,  however, 
exerted  upon  the  vasomotor  centres,  but  it  is  necessary  to  make  clear 
how  the  heart  behaves  under  these  conditions.  If  caffeine  raises  the 
blood-pressure,  there  necessarily  results  an  improvement  of  the  cardiac 
action,  for,  on  account  of  the  narrowing  of  the  vessels,  more  blood 
flows  back  into  the  heart. 

In  an  isolated  frog's  heart,  rendered  independent  of  indirect  in- 
fluence through  changes  in  the  blood-vessels,  it  is  not  possible  to  demon- 
strate that  there  is  any,  increase  in  the  work  done  against  the  normal 
resistance,  and  large  doses  quickly  exert  a  harmful  effect  on  the 
heart,  while  even  after  small  doses  the  pulse  volume  of  the  frog's 
heart  is  not  distinctly  increased  (Maki).  On  the  other  hand,  even 
after  small  doses  there  is  an  augmentation  of  the  " absolute  power" 
of  the  heart, — that  is,  it  is  able  to  empty  itself  against  a  greater 

istance  than  before  (Dreser1).  We  have  here  an  action  on  the 
iac  muscle  analogous  to  the  action  of  caffeine  on  voluntary 
muscles,  the  absolute  power  of  which  is  also  increased  by  caffeine 
(Dreser 2). 

Difference  in  Cardiac  Action  of  Caffeine  and  of  Digitalis. — In 
accordance  with  the  above,  the  action  of  caffeine  on  the  frog's  heart 
is  quite  different  from  that  of  the  digitalis  bodies.  In  contradistinc- 

>n  to  those  drugs,  caffeine  has  no  favorable  "diastolic"  action.    On 


£68  PHARMACOLOGY  OF  CIRCULATION 

the  contrary,  from  the  start  it  lessens  the  extent  of  relaxation  and 
thus,  especially  in  the  mammalian  heart,  diminishes  its  pulse  volume. 
This  results  from  the  fact  that  caffeine  increases  the  tendency  of  the 
cardiac  muscle  to  remain  contracted,  just  as  it  does  with  voluntary 
muscles,  and  at  the  same  tune  it  hinders  the  relaxation  of  the  heart 
in  diastole.  While  one  may  compare  the  heart  under  the  influence 
of  digitalis  with  a  pump  the  piston  of  which  makes  greater  excursions 
but  is  unable  to  overcome  any  greater  maximal  pressure,  under  the 
influence  of  caffeine  the  volume  of  blood  forced  out  by  single  contrac- 
tions is  at  no  time  increased,  but  the  heart  can  overcome  a  greater 
maximal  blood-pressure.  A  favorable  action  on  the  heart  could,  there- 
fore, result,  especially  when  there  is  an  abnormally  high  resistance  in 
the  vessels.  The  observations  of  Bock  on  the  "heart-lung"  circulation 
of  the  rabbit  are  in  accord  with  these  conclusions. 

Although,  on  the  other  hand,  Hedbom  observed  that  in  the  mammalian  heart, 
perfused  according  to  Langendorff,  caffeine  caused  both  an  increase  in  the  fre- 
quency and  a  distinct  increase  in  the  amplitude  of  the  heart-beat,  this  may  be 
explained  by  its  specific  power  to  dilate  the  coronary  vessels.  The  improved  blood 
supply  thus  obtained  increases  the  strength  of  the  contractions  in  the  artificially 
perfused  heart  to  such  a  degree  that  any  diminution  in  the  diastolic  relaxation 
is  compensated  for. 

Caffeine  accelerates  the  action  of  the  isolated  mammalian  heart  by 
a  direct  action  in  the  heart.  As  this  occurs  after  atropine  and  as  the 
vagus  nerve-ends  remain  excitable  (Wagner)  this  pulse  acceleration 
cannot  be  the  result  of  a  depression  of  the  inhibitory  mechanism,  but 
is  due  to  a  stimulation  of  the  cardiac  accelerator  mechanism.* 

The  acceleration  of  the  pulse  after  caffeine  is  well  developed  in  the 
first  stages  only  if  the  heart  is  beating  independently  of  the  control 
of  the  central  nervous  system.  On  the  other  hand,  in  the  intact 
animal  caffeine  excites  the  vagus  centre  just  as  it  does  other  nervous 
centres.  With  small  doses  this  effect  is  the  predominant  one,  so  that 
usually  at  the  start  the  pulse  is  retarded  if  the  vagi  are  intact.  In 
man  also  (Riegel,  Kunkel)  the  pulse  may  be  slowed  by  therapeutic 
doses  of  caffeine  (0.2-0.5  gm.).f  Only  after  larger  doses  does  the 
acceleration  of  the  pulse  occur,  this  being  a  result  of  a  direct  action 
on  the  heart. 

After  toxic  doses,  and  also  temporarily  after  the  intravenous  injec- 
tion of  the  small  doses,  in  experiments  on  animals,  the  heart  action 
becomes  feeble  and  arhythmic,  and  finally  fibrillation  of  the  heart 
develops  and  the  heart  stops  in  diastole. 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  43. 
1Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  24. 
•Dreser:  Arch.  f.  exp.  Path  u.  Pharm.,  1890,  vol.  27. 

*  [Like  digitalis  caffeine  also  by  its  action  on  the  intracardiac  motor  mechan- 
ism may  cause  or  aggravate  a  tendency  to  premature  contractions  (extra 
systoles). — TB.] 

•}•  [In  man  the  rule  is  that  caffeine  accelerates  the  pulse. — TB.] 


FACTORS  AFFECTING  THE  HEART  269 

Hedbom:  Skand.  Arch.  f.  Physiol.,  1898,  vol.  8. 

Johannson:   Diss.,  Dorpat,  1869. 

Kunkel:  Toxikologie,  Jena,  1899,  p.  576. 

Maki:  Diss.,  Strassburg,  1884. 

Riegel:  Verb.  d.  Kongr.  f.  inn.  Med.,  Wiesbaden,  1884. 

Wagner:  Diss.,  Berlin,  1885. 

OTHER  FACTORS  AFFECTING  THE  HEART  ACTION. — From  experi- 
ments on  the  surviving  mammalian  heart,  it  is  known  that  its  excita- 
bility and  capacity  for  work  depend  to  a  great  degree  on  the  tem- 
perature and  on  special  chemical  conditions, — that  is,  on  the  correct 
composition  of  the  perfusing  fluid.  A  considerable  rapidity  in  the 
flow  of  the  nutrient  solution  is  also  necessary  for  the  maintenance  of 
the  normal  chemical  processes  in  the  mammalian  heart,  for  it  would 
appear  that  the  demand  for  oxygen  made  by  the  actively  beating  heart 
necessitates  this  rapid  flow.  On  the  other  hand,  a  heart  may  beat 
for  hours  in  a  haemoglobin-free  fluid  or  in  blood  rich  in  carbon  mon- 
oxide (Strecker),  the  small  quantities  of  oxygen  absorbed  by  the  salt 
solution  being  sufficient  to  maintain  this  function.  However,  the 
power  of  the  contractions  of  the  mammalian  heart  and  its  capacity 
for  work  are  dependent  in  a  high  degree  upon  the  supply  of  oxygen, 
just  as  is  the  case  with  every  muscle  (Rohde). 

A  rapid  flow  through  the  vessels  of  the  heart  is  also  necessary 
to  remove  or  to  neutralize  those  metabolic  products,  resulting  from 
the  cardiac  activity,  which  exert  a  depressant  action  on  the  heart. 
Such  a  substance  is,  for  example,  carbon  dioxide,  the  accumulation 
of  which  in  the  heart  inhibits  its  activity. 

For  the  maintenance  of  the  chemical  equilibrium  in  the  heart,  we 
need  a  nutrient  medium  adjusted  properly  to  this  equilibrium.  Each 
smallest  alteration  in  the  proportions  of  the  chemical  constituents  of 
the  nutrient  solution — for  example,  the  loss  or  removal  of  any  of 
them,  especially  the  loss  or  diminution  of  the  calcium  salts — causes 
severe  disturbances,  just  as  in  all  other  susceptible  organs.  Especially 
in  the  heart  these  disturbances  are  quickly  and  clearly  manifested  by 
changes  in  its  automatic  activity. 

Physiological  sodium  chloride  solution  alone  is  not  capable  of 
maintaining  the  function  of  the  heart  for  any  considerable  period,  the 
heart  becoming  exhausted  and  being  harmfully  effected  by  it,  so  that 
its  excitability  and  functional  powers  gradually  fail  (Martins).  The 
heart  function  is  maintained  far  better  by  a  solution  containing  all 
the  salts  normally  present  in  the  blood, — e.g.,  those  of  the  blood  ash 
(Merunowitsch) .  As  solutions  which  besides  NaCl  and  a  calcium 
salt  also  contain  Na2C03  or  NaOH  act  more  favorably,  the  significance 
of  the  alkaline  salts  of  the  blood  may  be  sought  also  in  their  power 
of  neutralizing  acid  metabolic  products  (Gothlin).  According  to 
all  more  recent  investigations,  calcium  appears  especially  important. 
Ringer  was  the  first  to  show  that,  in  addition  to  common  salt,  CaCl  and 
!C1  must  be  present  in  the  nutrient  solution  in  order  to  obtain  the 


270  PHARMACOLOGY  OP  CIRCULATION 

best  possible  performance  by  the  heart.  An  improvement  in  the 
function  of  cold-  and  warm-blooded  hearts  results  from  the  addition 
of  calcium  to  a  solution  containing  enough  NaCl  to  maintain  the 
proper  osmotic  pressure.  Such  addition  causes  increased  and  more 
energetic  contractions,  but  gradually  the  relaxation  becomes  incom- 
plete and  the  heart-beats  thus  become  less  efficient  (Langendorff) . 
Potassium,  on  the  other  hand,  if  added  by  itself  to  the  NaCl  solution, 
favors  relaxation  and  ultimately  causes  a  diastolic  standstill.  Calcium 
and  potassium  are  thus  seen  to  work  antagonistically  to  each  other  and, 
when  both  are  present,  to  compensate  each  other.  In  the  proportions 
used  in  Ringer's  solution  the  calcium  preponderates.  Under  the  con- 
ditions obtaining  in  the  blood  in  which  both  of  these  ions  are  present, 
we  are,  therefore,  dealing  with  a  compensated  calcium  action  (Ringer,, 
Gross) . 

BIBLIOGRAPHY 

Gothlin:   Skand.  Arch.  f.  Physiol.,  1901.  vol.  12. 

Gross:   Pfliiger's  Arch.,  1903,  vol.  99. 

Kronecker:   Festschrift  f.  C.  Ludwig,  Leipzig,  1875. 

Langendorff  u.  Hueck:   Pfliiger's  Arch.,  1903,  vol.  96. 

Martius:   Du  Bois'  Arch.  f.  Physiol.,   1882. 

Merunowitsch :   Ludwig's  Arbeiten,  1876,  vol.  10. 

Ringer:   Journ.  of  Physiol.,  1887,  vol.  8. 

Rohde:   Ztschr.  f.  physiol.  Chemie,  1910,  vol.  86,  p.  181. 

Straub:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45. 

Strecker:  Pfliiger's  Arch.,  1900,  vol.  80. 

PHARMACOLOGICAL  ACTION  ON  THE  VESSELS 

Like  the  heart,  the  vessels  have  a  double  innervation  through  the 
vasoconstrictors  and  vasodilators,  their  interplay  maintaining  the  com- 
pensatory regulations  in  the  circulation  by  which  the  blood  supply  of 
the  vital  organs  is  preserved  (see  page  231  ff.).  With  the  assist- 
ance of  the  vasomotor  centres,  the  regulative  constriction  of  other 
vascular  systems  is  brought  about  when  any  vascular  system  is  dilated, 
and  in  the  same  fashion  vasoconstriction  of  one  system  is  compensated 
for  by  vasodilatation  in  others,  so  that  the  blood  supply  of  the  organs 
can  vary  within  large  limits,  according  to  their  changing  needs, 
without  any  alteration  in  the  general  blood-pressure.  In  numerous 
pharmacological  actions  a  similar  mechanism  is  called  into  play,  so 
that  under  their  influence  only  the  distribution  of  the  blood  is 
altered,  the  pressure  in  the  aorta  remaining  constant. 

Probably  the  vasoconstrictors  as  well  as  the  vasodilators  control 
these  compensations  in  the  vascular  system.  Their  cooperation  would 
appear  to,  be  secured  by  means  of  a  reciprocal  intracentral  inhibition, 
so  that,  for  example,  decreased  tonus  of  the  vasoconstrictor  centres 
automatically  results  in  a  stimulation  of  the  vasodilator  centres.  The 
two  mechanisms  thus  normally  never  act  in  opposition,  but  always 
together. 

As  a  result  of  this  double  innervation  any  change  in  vessel  calibre 
— for  example,  relaxation  in  a  particular  vascular  system — may  occur 


PHARMACOLOGY  OF  THE  VESSELS  271 

in  two  ways, — either  by  depression  of  the  vasoconstrictors  or  by  stimu- 
lation of  the  vasodilators.  Both  of  these  effects  may  be  due  to  an 
action  on  the  centres  or  on  the  peripheral  mechanism. 

There  are  also  in  the  vessel  walls  peripheral  vasomotor  nerve- 
ganglia,  pharmacological  action  on  which  cannot  be  differentiated 
from  that  on  the  terminal  mechanisms.  The  existence  of  these  periph- 
eral vasomotor  nerve-ganglia  is  proved  by  the  fact  that,  even  after 
separation  from  the  central  nervous  system, — for  example,  after 
section  of  the  vasomotor  nerves, — certain  vascular  systems  do  not 
remain  maximally  dilated  but  gradually  regain  their  power  to  react. 
The  significance  of  this  peripheral  vascular  tonus  is  best  demonstrated 
in  the  experiments  of  Ewald  and  Goltz,  in  which,  after  destruction 
of  the  dorsal  and  sacral  cord  and  section  of  the  sciatic  of  the  dogr 
there  developed  in  the  lower  extremities  a  vascular  tonus  independent 
of  all  central  influence.  The  intestinal  vessels  also,  after  section  of 
the  splanchnics,  gradually  regained  their  tonus  with  the  assistance- 
of  peripheral  mechanisms,  and  the  blood-pressure  was  re-established. 

Finally,  alterations  of  vessel  calibre  depend,  in  the  last  instance,, 
on  the  muscles  in  the  arterial  walls.  An  example  of  a  probably 
direct  action  on  these  muscles  may  be  seen  in  the  vasoconstriction 
produced  by  barium  salts.  However,  it  is  hardly  possible  to  differ- 
entiate with  certainty  between  a  pharmacological  action  on  nerve- 
endings  in  the  vessel  wall  and  that  on  their  muscles. 

All  these  changes  in  the  calibre  of  the  vessels  may  affect  only  one 
vascular  system  or  many  at  one  time.  In  such  case,  the  central  action 
on  the  vessel  innervation  and  the  peripheral  changes  in  the  vessel  wall 
produced  by  one  and  the  same  drug  may  cause  similar  or  opposite 
effects,  so  that,  for  example,  vasodilatation  in  the  kidney,  due  to  a 
peripheral  action,  may  occur  at  the  same  time  with  vasoconstriction 
in  other  situations,  this  latter  being  the  result  of  a  central  action.  It 
is  thus  comprehensible  that  the  distribution  of  the  blood  may  be 
affected  by  drugs  in  the  most  manifold  fashion. 

That  under  these  conditions  the  aortic  pressure  remains  un- 
changed is  due  to  the  already  discussed  compensating  mechanism  of 
the  circulation,  the  behavior  of  the  vessels  of  the  intestine,  the  liver, 
and  the  spleen  being  of  decisive  importance  for  this  power  of  accom- 
modation. On  account  of  its  great  capacity,  the  portal  system  is  able 
to  furnish  enough  blood  for  the  filling  of  the  other  vascular  systems, 
or,  on  the  other  hand,  as  a  result  of  its  great  distensibility,  it  is  able 
to  accommodate  blood  forced  out  from  other  parts  of  the  body,  thus 
compensating  for  vasoconstriction  elsewhere. 

Only  by  the  investigation  in  detail  of  the  different  vascular  sys- 
tems— for  example,  by  means  of  plethysmography — is  it  possible  to 
recognize  these  variations  in  the  distribution  of  the  blood,  as  long  as. 
in  their  early  stages  their  effect  on  the  aortic  pressure  is  compensated 


272  PHARMACOLOGY  OF  CIRCULATION 

for  by  the  compensatory  behavior  of  the  different  vascular  systems. 
Only  very  pronounced  vasomotor  effects  cause  changes  in  the  aortic 
pressure. 

By  stimulation  of  the  splanchnic  Mall  was  able  to  transfer  27  per  cent, 
of  the  total  blood  contents  of  a  dog  from  the  portal  circulation  into  other 
systems,  the  splanchnic  stimulation  causing  constriction  not  only  of  the  arteries 
but  also  of  the  veins  in  the  portal  system  (Schmid). 

The  SPLANCHNIC  acts  as  the  chief  regulator  of  this  compensating 
function.  For  this  reason  the  blood-pressure  in  the  aorta  remains 
normal,  even  if,  for  example,  the  vessels  of  the  skin  be  ever  so 
extremely  dilated  by  antipyrine.  However,  the  total  cross-section 
of  the  arterial  tree  may  be  maintained  constant  only  as  long  as  the 
portal  system  remains  under  the  control  of  its  vasomotor  inner- 
vation,  for  any  marked  dilatation  of  the  hepatic  and  intestinal  vessels 
cannot  be  compensated  for,  and,  therefore,  if  vasomotor  depressants, 
such  as  certain  bacterial  toxins,  act  on  the  centres  controlling  the 
visceral  vessels,  this  compensation  does  not  occur  and  the  aortic 
pressure  sinks. 

Constriction  of  the  visceral  vessels  mechanically  and  reflexly  forces  the 
blood  into  other  vascular  systems.  If,  for  example,  the  vessels  of  the  skin  and 
muscles  are  dilated  while  simultaneously  the  splanchnic  vessels  are  constricted, 
it  may  be  a  question  whether  this  be  due  to  a  direct  action  in  dilated  systems 
or  to  expulsion  of  the  blood  from  the  visceral  vessels  into  those  of  the  skin  and 
muscles.  This  point  must  be  especially  remembered  in  considering  the  early 
stages  of  the  action  of  alcohol  and  ether,  as  also  in  connection  with  the  dilatation 
of  the  cutaneous  vessels  in  atropine  poisoning. 

In  the  different  species  the  relative  importance  quantitatively  of  the  different 
vascular  systems  can  vary  greatly.  In  particular,  it  is  difficult  to  compare  the 
cutaneous  vessels  of  man  with  those  of  the  animals  used  in  our  experiments,  for 
in  man  the  skin,  as  an  important  organ  for  the  loss  of  heat,  plays  a  quite 
different  r6le  from  that  played  by  the  hide  of  these  animals,  and  accordingly 
in  man  the  cutaneous  vessels  are  much  more  numerous  and  more  subject  to 
nervous  influences.  Moreover,  the  different  relative  size  of  the  extremities  and 
the  trunk  in  man  and  in  the  small  laboratory  animals  is  a  further  factor  to  be 
considered.  On  the  other  hand,  the  length  of  the  alimentary  canal  has  an  effect 
on  the  influence  exerted  by  the  splanchnic  vessls  on  the  distribution  of  the  blood. 
For  this  reason,  after  section  of  the  splanchnic,  the  blood-pressure  does  not  fall 
as  much  in  the  dog  as  in  the  rabbit. 

As  a  result  of  the  above-described  compensatory  mechanism  in  the 
circulation,  we  may  expect  only  an  alteration  in  the  distribution  of 
the  blood,  without  change  in  the  general  blood-pressure,  to  result 
from  the  moderate  vasomotor  effects  of  drugs.  Only  if  a  pharmaco- 
logical action  overcomes  this  regulation  will  the  circulatory  condition 
in  the  whole  body  be  affected  and  the  carotid  pressure  be  changed. 

BIBLIOGRAPHY 

Mall:  Dubois'  Arch.,  1892,  p.  409. 

Schmid:  Habilitationsschrift,  Breslau,  1907. 

Bchmid:  Pfltiger's  Arch.,  1909,  vol.  126,  p.  165. 


CENTRAL  VASOCONSTRICTORS 


273 


CENTRALLY  ACTING  VASOCONSTRICTING  DRUGS 

STRYCHNINE. — The  excitability  of  the  vasoconstrictor  centres  is 
augmented  by  strychnine  in  the  same  way  in  which  the  spinal  reflexes 
controlling  motor  functions  are  rendered  over-excitable  by  this  drug. 
With  the  maximal  development  of  the  strychnine  action,  therefore,  a 
tetanus  of  the  muscles  of  the  vessel  walls  occurs  simultaneously  with 
the  outbreak  of  the  tetanus  of  the  striped  muscles,  and  thus  the  aortic 
pressure  is  tremendously  raised.  This  vascular  cramp  is,  however, 
independent  of  the  tonic  contractions  of  the  voluntary  muscles  for 
it  occurs  in  the  curarized  animal  (see  Fig.  29).  The  vagus  centre  is 
also  stimulated  simultaneously  with  the  vasomotor  centres  (8.  Mayer). 


LI  M  i  i  t  i  i  M  M  i  i  i  i  r  i  n  i  i  i  i  »  i  M  i  i  i  i  M  i  n  1 1  i  i  i  i  .1 

Strychnine  nitr.  0.6  trig.  p.  Kilo 

FIG.  29. — The  effect  of  strychnine  on  the  blood-pressure  of  a  curarized  cat. 

After  division  of  the  cord  in  the  neck,  strychnine  raises  the  blood-pressure 
a  much  slighter  extent,  but  some  rise  does  occur,  especially  in  young  animals, 
so  that,  after  isolating  the  vascular  system  from  the  main  centres  in  the  medulla, 
strychnine  may  be  used  to  demonstrate  the  existence  of  accessory  vasomotor 
centres  in  the  spinal  cord  (Schlesinger).  On  the  heart,  strychnine  exerts  a 
depressing  influence  only  in  doses  which  are  much  larger  than  those  causing 
convulsions  ( Igersheimer ) . 

All  of  the  vascular  systems  are  by  no  means  equally  affected 
by  strychnine.  On  the  contrary,  practically  only  the  vessels  in  the 
portal  system  are  constricted,  as  may  be  shown  by  the  simple  inspection 
of  the  exposed  intestines.  Plethysmographically,  diminution  in  their 
volume — for  example,  in  the  kidney — may  be  demonstrated  while  the 
peripheral  vessels  may  be  shown  to  be  dilated  (Wertheimer  et  Dele- 
zenne). 
18 


274  PHARMACOLOGY  OF  CIRCULATION 

BIBLIOGRAPHY 

Igersheimer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  54,  p.  73. 
Mayer,  S.:  Wien.  sitzungsbericht  d.  Akad.,  1871,  vol.  54,  part  2. 
Schlesinger:  Wien.  med.  Jahrbuch,  1873. 
Wertheimer  et  Delezenne:  Compt.  rend,  de  la  Soc.  de  Biol.,  1897,  p.  633. 

CAFFEINE'S  action  on  the  vasomotor  centres  is  analogous  to  that 
of  strychnine,  just  as  large  doses  of  caffeine  cause  convulsions.  How- 
ever, the  stimulation  of  the  vasomotor  centres  by  caffeine  does  not 
result  in  as  marked  a  rise  in  pressure,  because  the  action  of  the 
caffeine  on  these  centres  is  complicated  by  the  influence  exerted  at 
the  same  time  on  the  frequency  of  the  pulse  and  on  the  pulse  volume 
of  the  heart.  In  animals  it  may  be  demonstrated  that  especially 
medium-sized  doses  cause  an  increase  in  blood-pressure,  while  still 
larger  doses  produce  no  change  in  the  blood-pressure.  Very  large 
doses,  as  well  as  very  rapid  direct  injection  of  the  drug  into  the 
veins,  cause  a  fall  in  pressure,  resulting  from  the  depression  of  the 
functional  power  of  the  heart,  which  is  undoubtedly  caused  by  the 
strong  concentration  of  caffeine  acting  directly  on  the  heart  (see 
p.  268). 

Besides  acting  on  the  vasomotor  centres,  caffeine  acts  also  on  the 
vessels  in  the  periphery.  This  action  on  the  vessel  walls  is,  however, 
the  opposite  of  its  central  action,  for  by  its  peripheral  action  it  dilates 
the  vessels  of  the  heart,  kidney,  and  brain.  The  two  dimethylxan- 
thines,  theobromine  and  theophylline,  also  possess  this  peripheral 
vasodilator  action  (see  p.  330),  while  their  action  on  the  vasoconstrictor 
centres  is  much  less  pronounced,  although  they,  in  their  chemical 
nature  and  pharmacological  action,  closely  resemble  caffeine. 

CAMPHOR,  PICROTOXIN,  and  other  medullary  convulsants  also 
stimulate  the  vasoconstrictor  centres.  Doses  large  enough  to  cause 
convulsions  raise  the  blood-pressure,  for  the  constriction  of  the 
visceral  vessels  overcomes  the  regulatory  mechanism  which  ordinarily 
prevents  any  alteration  of  the  general  pressure  (Wiedemann') .  In 
such  case  the  blood  distribution  is  similar  to  that  resulting  from  the 
action  of  strychnine  and  caffeine.  It  is  probable  that  camphor  can 
exert  a  favorable  action  on  depressed  vasomotor  centres,  for  in  experi- 
ments on  chloralized  animals  these  centres,  which  had  become  insus- 
ceptible to  stimulation  by  asphyxia  or  by  sensory  reflexes,  again 
became  excitable  (Alexander-Lewin) .  Simultaneously  with  the  vaso- 
constriction  in  the  interior  of  the  body,  the  cutaneous  vessels  are 
dilated. 

BIBLIOGRAPHY 

Alexander-Lewin :  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  226. 
Wiedemann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1876,  vol.  6,  p.  216. 

ALCOHOL  affects  the  calibre  of  the  vessels  in  different  organs  in  a 
very  manifold  fashion.  The  cutaneous  vessels  are  dilated  even  by 
small  doses,  while  in  the  first  phases  of  its  action  the  visceral  vessels 


CENTRAL  VASOCONSTRICTORS  275 

appear  to  be  constricted.  It  is  probable  that  the  dilatation  of  the 
cutaneous  vessels  is  only  partly  the  result  of  the  constriction  of  the 
visceral  vessels.  Like  many  other  pharmacologically  closely  related 
substances,  alcohol  possesses  the  power  of  slightly  lessening  the  central 
vasoconstrictor  tonus  for  the  cutaneous  vessels,  but  the  accompanying 
constriction  of  the  visceral  vessels,  which  is  produced  by  small  doses 
of  alcohol,  is  in  part  due  to  a  peripheral  action,  and,  according  to 
Dixon,  also  in  part  a  result  of  central  action.  In  consequence  of  these 
opposite  effects  on  the  different  vascular  systems,  a  change  in  the 
blood  distribution  but  no  important  change  in  the  blood-pressure  may 
be  expected  to  result  from  small  doses  of  alcohol ;  but  after  intravenous 
injection  of  appropriate  doses  the  vasoconstriction  in  the  splanchnic 
system  may  be  pronounced  enough  to  raise  the  pressure  in  the  carotid 
(Dixon,  Haskovec,  Kochmann),  while  with  still  larger  doses  alcohol 
dilates  not  only  the  cutaneous  vessels  but  also  all  the  others,  and,  as 
the  splanchnic  vessels  are  affected  with  the  others,  the  blood-pressure 
falls. 

BIBLIOGRAPHY 

Dixon:  Journ.  of  Physiol.,  1907,  vol.  35,  p.  346. 

Haskovec:  Arch,  de  m6decine  experim.,  1901,  vol.  13,  p.  539. 

Kochmann:  Arch,  intern,  de  Pharmacodyn.,  1904,  vol.  13,  p.  329. 

ETHER. — According  to  Derouaux,  ether  similarly  affects  the  dis- 
tribution of  the  blood.  In  the  dog  a  slight  rise  in  blood-pressure  is 
observed  after  subcutaneous  injection,  but  this  is  much  more  marked 
after  the  intravenous  injection  of  a  properly  chosen  dose.  As  shown 
by  the  plethysmographic  curves,  the  visceral  vessels  are  constricted  and 
those  in  the  periphery  dilated  during  the  period  of  increased  blood- 
pressure.  The  early  rise  in  blood-pressure  during  narcosis  and  the 
improvement  of  the  heart  action  following  hypodermic  injections  of 
ether  (seep. 257)  are  to  be  explained  as  reflex  actions  caused  by  the 
irritation  produced  by  the  ether  in  the  mucous  membranes  or  at  the 
point  of  injection.  [This  conclusion,  that  this  is  the  sole  cause  of  the 
rise  in  blood-pressure  observed  in  narcosis,  appears  to  the  translator 
not  justified  either  by  the  clinical  or  the  experimental  evidence.] 

BIBLIOGRAPHY 
erouaux:  Arch,  intern,  de  PTiarmacodyn.  et  de  Therap.,  1909,  vol.  19,  p.  63. 

The  behavior  of  the  cutaneous  and  visceral  vessels  during  the  early 
of  the  action  of  alcohol  and  ether  is  a  good  example  of  the 
luantitative  differences  in  the  reaction  of  the  different  vasomotor 
mtres  to  identical  pharmacological  influences.  The  cutaneous  ves- 
sels react  readily  to  the  dilating  action  of  the  narcotics,  but  the 
splanchnic  vessels  only  after  much  larger  doses.  This  especial  sus- 
ceptibility of  the  cutaneous  vessels  to  the  dilating  action  of  centrally 
depressing  drugs  is  best  developed  in  the  vessels  of  the  face.  The 


276  PHARMACOLOGY  OF  CIRCULATION 

other  cutaneous  vessels  are  dilated  only  after  larger  dosage,  while 
the  vessels  in  other  parts  of  the  body  are  the  last  to  be  affected. 
Of  such  causation  is  the  flushing  of  the  face  during  ether  narcosis  or 
at  the  start  of  chloroform  narcosis  and  that  caused  by  the  drinking 
of  wines  with  strong  bouquet,  as  well  as  by  morphine  in  certain  indi- 
viduals. It  is  most  strongly  expressed  during  the  action  of  amyl 
nitrite. 

The  antipyretics  and  atropine  cause  redness  of  the  skin  in  an 
especially  elective  fashion,  no  other  vessels  being  dilated  even  by 
quite  large  doses.  One  might  be  tempted  to  attribute  this  action  of 
the  antipyretics  to  depression  of  the  vasoconstrictor  centres,  and  in 
the  case  of  atropine,  with  its  power  of  acting  as  a  general  central 
stimulant,  to  stimulation  of  the  vasodilator  centres.  It  is  not  possible, 
however,  to  decide  positively  between  these  two  possible  seats  of  action. 
Perhaps  both  mechanisms  are  simultaneously  influenced  by  these  drugs 
but  in  different  directions,  just  as  physiologically  these  centres  ordi- 
narily compensate  each  other  as  a  result  of  their  antagonistic 
actions. 

CENTRALLY  ACTING  VASODILATING  DRUGS 

NARCOTICS. — In  large  doses  narcotics  of  the  alcohol  group,  espe- 
cially chloroform  or  chloral  hydrate,  and  also  numerous  alkaloids, — 
e.g.,  morphine  in  toxic  doses, — cause  a  gradual  diminution  in  the 
excitability  and  finally  a  general  paralysis  of  the  vasomotor  centres, 
the  pulse  becoming  soft  and  the  blood-pressure  gradually  falling. 
The  same  is  true  of  numerous  other  central  depressants  and  especially 
of  bacterial  toxins, — for  example,  diphtheria  toxin. 

AMYL  NITRITE  is  the  most  powerful  of  these  vasodilating  drugs, 
the  inhalation  of  the  fumes  of  2-5  drops  causing  almost  instantaneous 
flushing  and  a  feeling  of  warmth  of  the  face,  pulsation  of  the  carotids, 
and  acceleration  of  the  heart-beats.  At  the  same  time  the  head 
swims  and  a  feeling  of  slight  drunkenness  develops.  The  brilliant 
redness  of  the  skin  extends  from  the  face  over  the  throat  and  chest, 
but  rarely  extends  below  the  waist.  After  a  few  minutes  the  effects 
of  small  doses  pass  off. 

The  temperature  of  the  profusely  reddened  skin  is  raised,  thermo- 
electric measurements  indicating  a  rise  in  temperature  of  the  skin  of 
as  much  as  3°  C.  (Arntz,  Lahnsteiri). 

In  man  it  has  been  demonstrated  that  the  vasodilatation  produced 
by  small  doses  is  confined  to  the  skin  of  the  head  and  trunk  and  to 
the  vessels  of  the  brain,  while  probably  the  coronary  vessels  are  also 
affected  even  by  small  doses.  The  dilatation  may  be  particularly 
well  demonstrated  in  the  rabbit's  ear,  especially  in  tracheotomized 
subjects,  as  by  this  means  it  is  possible  to  exclude  the  disturbing  re- 
flexes due  to  the  action  of  the  irritating  vapor  on  the  nasal  mucous 
membrane.  The  participation  of  the  cerebral  vessels  may  be  proved 
by  inspection  of  the  pia  mater  of  trepanned  animals,  or  by  measuring 


CENTRAL  VASODILATORS  277 

the  blood  flowing  out  of  the  cerebral  veins  ( Gartner  u.  ~Wagner,  Schiil- 
ler,  Schramm,  Hurthle).  Mo&so  was  able  to  observe  an  increase 
in  the  volume  of  the  brain  in  a  case  with  a  cranial  defect.  Plethys- 
mographic  curves  were  taken  at  the  same  time  from  the  forearm  and 
foot,  and  it  was  found  that  vasodilatation  in  the  forearm  occurred 
somewhat  later  than  the  increase  of  blood  flow  to  the  brain,  while 
during  the  action  of  the  drug  the  volume  of  the  foot  was  constantly 
diminished  below  the  normal. 

The  radial  pulse  is  larger  and  softer  during  the  action  of  amyl 
nitrite,  its  rate  rising,  after  a  few  inhalations,  approximately  from 
75  to  98  in  the  minute.  Animal  experiments  similarly  show  a  fall 
in  blood-pressure  and  acceleration  of  the  pulse. 

That  the  vasodilatation  is  due  primarily  to  an  action  on  the 
centres  was  proved  by  the  experiments  of  Filehne,  who  caused  rabbits 
to  inhale  amyl  nitrite,  the  blood  circulation  in  the  brain  and  medulla 
being  part  of  the  time  maintained  and  part  of  the  time  interrupted 
by  clamping  the  internal  carotids  and  the  subclavian  arteries.  The 
vasodilatation  in  the  rabbit's  ear  did  not  occur  when  the  circulation 
of  the  brain  was  interrupted,  although  the  blood  flowing  through  these 
vessels  contained  the  drug.  In  other  experiments  in  which  the  circu- 
lation through  the  centres  was  intact  and  in  which  the  drug  reached 
them,  the  vessels  of  the  ear  dilated  even  when  these  vessels  were  sup- 
plied with  blood  containing  none  of  the  drug. 

In  large  quantities,  however  (quite  independently  of  its  action 
on  the  centres),  amyl  nitrite  depresses  the  tone  of  the  vessels  by  a 
peripheral  action.  This  peripheral  vasodilating  action  of  amyl  nitrite 
is  perhaps  of  considerable  therapeutic  significance.  That  such  periph- 
eral action  occurs  is  proved  by  the  fact  that  the  blood-pressure  falls 
during  inhalation  of  the  drug,  even  when,  by  previous  section  of  the 
cervical  cord  or  by  ligation  of  all  arteries  supplying  the  brain,  the 
principal  vasomotor  centres  have  been  eliminated  (Lauder-Brunton,1 
8.  Mayer  u.  Friedrich). 

That  in  this  case  the  action  takes  place  in  the  vessel  wall  and  not  in  the 
subsidiary  centres  in  the  cord  is  indicated  by  the  results  of  perfusion  of  isolated 
organs,  as  also  by  the  fact  that  injection  of  a  nitrite  into  the  carotid  causes  at 
first  dilatation  of  the  vessels  of  the  brain  alone  (Biedl  u.  Reiner). 

In  toxic  doses  the  blood-pressure  is  markedly  lowered,  and  the  rapid  pulse 
becomes  weak,  but  this  is  not  due  to  an  impairment  of  the  heart's  function, 
for  the  isolated  heart  is  depressed  only  by  still  larger  doses  (Bock  et  al.).  The 
fall  in  pressure  and  the  enfeeblement  of  the  pulse  after  toxic  doses  are,  therefore, 
only  the  results  of  a  general  vasoparesis. 

As  after  section  of  the  cervical  vagi  the  increased  frequency  of  the 
heart  action  does  not  occur,  it  is  clear  that  the  acceleration  of  the 
pulse  is  also  an  indirect  effect  due  to  the  depression  of  the  cardio- 
inhibitory  centre,  this  resulting  automatically  from  the  fall  in  blood- 
pressure,  for  in  Filehne's  experiments  the  acceleration  of  the  pulse 
disappeared  if  the  blood-pressure  was  restored  to  the  normal  by  tem- 
Tary  clamping  of  the  abdominal  aorta. 


278  PHARMACOLOGY  OF  CIRCULATION 

When  the  cardiac  nerves  are  intact,  it  is  a  general  rule  that  the  frequency 
of  the  pulse  increases  with  the  fall  in  the  general  blood-pressure.  The  importance 
of  this  regulatory  mechanism  may  be  especially  well  demonstrated  with  amyl 
nitrite  if  its  effects  on  the  blood-pressure  in  the  dog  and  rabbit  be  compared. 
In  the  dog  the  blood-pressure  is  only  moderately  lowered  by  this  drug,  because, 
simultaneously  with  the  vasodilatation,  the  pulse  becomes  much  more  rapid.  In 
the  rabbit,  on  the  other  hand,  as  its  vagus  tone  from  the  beginning  is  weak, 
the  pulse-rate  is  much  less  increased,  and  the  blood-pressure,  therefore,  markedly 
falls  (Lauder-Brunton"),  In  man,  even  after  small  doses  the  pulse  is  markedly 
accelerated. 

Toxic  effects  result  from  the  continued  inhalation  of  amyl  nitrite,  while 
nausea  and  vomiting  are  sometimes  observed  even  after  small  doses.  Such  grave 
symptoms  as  fainting  and  collapse  after  large  doses  are  due  to  the  general 
vasoparesis.  Grave  poisoning  has  been  seldom  observed  in  man,  as  the  effects 
resulting  from  the  inhalation  pass  off  very  rapidly,  and  as  amyl  nitrite  is  only 
slowly  absorbed  from  the  stomach,  so  that  3  gm.,  in  fact  even  12  gm.,  taken  by 
mouth  have  not  caused  fatal  poisoning  (Rosen).  In  animal  experiments  long- 
continued  administration  of  large  amounts  of  amyl  nitrite  causes  convulsions, 
as  well  as  a  transformation  of  hsemoglobinse  into  methsemoglobin,  an  action 
which  is  characteristic  of  all  nitrites  (Gamgee,  Giacosa) . 

This  action  on  the  vessels  is  a  nitrite  action,  although  other  amyl 
ethers  dilate  the  vessels, — for  example,  amyl  chloride,  which,  accord- 
ing to  Hay,  may  be  used  for  the  same  indications  as  amyl  nitrite. 
Ethyl  alcohol  and  other  narcotics  of  this  group  also  possess  a  similar 
action.  However,  the  vasodilatation  resulting  from  very  small  doses, 
which  is  characteristic  of  amyl  nitrite,  as  well  as  the  formation  of 
methgemoglobin  after  large  doses,  is  dependent  on  the  nitrite  radical, 
for  the  salts  of  nitrous  acids,  such  as  sodium  nitrite,  produce  the  same 
pronounced  effect  on  the  vascular  systems. 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  158. 

Biedl  u.  Reiner:   Pfliiger's  Arch.,  1900,  vol.  79,  p.  158. 

Filehne:  Dubois'  Arch.  f.  Physiol.,  1879,  p.  386. 

Filehne:  Pfliiger's  Arch.,  1874,  vol.  9,  p.  470. 

Gartner  u.  Wagner:  Wiener  med.  Woch.,  1887. 

Gamgee:  Transact.  Royal  Soc.,  Edinburgh,  1868. 

Giacosa:  Ztschr.  f.  physiol.  Chemie,  1879,  vol.  3,  p.  54. 

Hay:  The  Practitioner,  1883. 

Hiirthle:  Pfluger's  Arch.,  1889,  vol.  44,  p.  561. 

Lahnstein:  Diss.  Wiirzburg.  1886. 

1  Lauder-Brunton :  Ber.  d.  Kgl.  Sachsischen  Ges.  d.  Wiss.,  1869,  vol.  21,  p.  285. 

*  Lauder-Brunton :    Jour,  of  Anat.  and  Phys.,  1870. 

Mayer,  S.,  u.  Friedrich:  Arch.  f.  exp.  Path.  u.  Pharm.,  1875,  vol.  5,  p.  55. 

Mosso:  Der  Kreislauf  d.  Blutes  in  menschl.  Gehirn,  Leipzig,  1881;  Die  Temperatur 

des  Gehirns,  Leipzig,  1894. 
Rosen:  Zbl.  f.  inn.  Med..  vol.  9,  p.  777. 
Schilller:  Berl.  klin.  Woch..  1874. 
Schramm:  Diss.,  Strassburg,  1874. 

PERIPHERALLY  ACTING  VASOCONSTRICTORS 
Pharmacological  action  in  the  vessel  walls  may  be  due  to  an  action 
on  the  nervous  elements  in  the  vessel  wall  or  to  an  action  on  the  con- 
tractile substance.    However,  we  possess  no  methods  which  enable  us 


PERIPHERAL  VASOCONSTRICTORS  279 

t 

to  differentiate  between  these  two  possible  seats  of  action  in  periph- 
eral vasoconstriction  or  dilatation. 

Epinephrin,  cocaine,  and  the  digitalis  bodies  stimulate  the  tone  of 
all  vessel  walls  [pulmonary  and  coronary  vessels? — TR.]  In  1895 
Oliver  and  Schaefer,  and  at  the  same  time  Czybulski  and  Szymonovicz, 
discovered  that  intravenous  injections  of  extracts  of  the  suprarenal 
glands  caused  an  enormous  rise  in  the  blood-pressure. 

EPINEPHRIN. — Immediately  after  this  Moore  demonstrated  that  the  active 
substance  was  present  only  in  the  medullary  portion  of  the  glands,  and  that  it 
was  identical  with  .a  chromogenic  substance,  described  by  Vulpian  as  early  aa 
1856,  possessing  striking  color  reactions, — green  coloration  with  iron  chloride 
on  the  addition  of  alkalies,  or  with  iodine  or  chlorine  water  a  pink-carmine  color. 
These  reactions  suggested  brenzcatechin,  and  v.  Ftirth  succeeded  in  preparing 
from  this  chromogen,  a  substance  which  in  its  behavior  agreed  with  brenz- 
catechin. The  crystallized  active  substance  was  first  prepared  in  1901  by 
Takamine  and  named  by  him  adrenaline.  Other  authors  have  given  it  the  names 
of  suprarenin,  paranephrin,  epinephrin,  epirenan,  etc.  [As  the  council  of 
Pharmacy  and  Chemistry  of  the  A.M.A.  has  recommended  "  epinephrin  "  as  the 
preferable  name,  this  name  will  be  used  throughout  this  translation.]  This 
substance,  having  the  empiric  formula  C9H13N03,  is  a  base  which  is  soluble  in 
water  and  readily  decomposes  in  alkaline  solution,  the  solutions,  like  those  of 
brenzcatechin,  turning  first  red  and  then  brown  when  exposed  to  the  action  of 
light. 

The  constitution  of  epinephrin  has  been  determined  as  that  of  a  brenzcate- 
chin derivative  of  relative  simple  structure.  It  is  an  aminoalcohol  (OH)2C8H, 
CH  OH  CH2  NH  CHa 

HO  /\  CH  OH  CH2  NH  CH, 

HO  I 

which  may  be  prepared  by  reduction  of  methylaminoacetobrenzcatecnin. 

Stoltz  and  Dakin  have  succeeded  in  synthetically  preparing  epinephrin  and 
a  series  of  related  brenzcatechin  derivatives,  which,  according  to  Loewi  and  Hans 
Meyer,  possess  an  action  fully  analogous  to  that  of  the  natural  alkaloid.  This 
synthetic  preparation  may  be  obtained  under  the  name  of  suprareninum  syn- 
theticum. 

The  natural  alkaloid  is  Isevorotatory.  The  synthetically  prepared  1-epi- 
nephrin  is  equally  as  active  as  this,  while  the  action  of  r-epinephrin  is  12-15 
times  weaker.  Recently  A.  Frb'hlich  found  that  very  large  doses  of  the  dextro- 
rotatory alkaloid  so  affected  the  circulation  that  even  one  or  more  milligrammes 
of  the  Isevorotatory  epinephrin  produced  no  effect  on  the  blood-pressure. 

The  rise  in  blood-pressure  is  caused  by  the  extreme  constriction 
of  the  smallest  arteries  due  to  direct  action  on  the  vessel  walls.  Sec- 
ondarily, a  direct  and  unusually  powerful  stimulating  effect  on  the 
heart,  which  has  already  been  discussed,  plays  a  role  in  the  pro- 
duction of  this  rise.  The  proof  that  the  vasoconstriction  is  due  to 
peripheral  action  is  furnished  by  experiments  in  which  the  rise  in 
blood-pressure  occurred  after  the  cervical  cord  had  been  severed 
and  the  spinal  cord  pithed,  or  after  complete  elimination  of  the  vaso- 
motor  centres  by  means  of  chloral  (Velich,  Gottlieb1).  Similarly, 
constriction  of  the  separate  vascular  systems  occurs  after  these  are 
rendered  independent  of  the  vasomotor  centres  by  section  of  their 
nerves  (Fr.  Pick,  Loewi  and  H.  Meyer).  In  artificial  perfusion 


280  PHARMACOLOGY  OF  CIRCULATION 

of  surviving  organs  the  peripheral  action  on  the  vessels  is  expressed 
by  retardation  or  even  by  a  complete  stoppage  of  the  flow,  which 
may  occur  even  after  maximal  dilatation  (Gottlieb2).  The  direct 
action  on  the  tone  of  the  arterial  walls  may  be  shown  in  an  especially 
instructive  manner  by  experiments  on  isolated  circular  strips  of  the 
arteries.  By  the  use  of  Ringer's  solution  kept  at  body  temperature, 
these  may  survive  for  days  and  maintain  their  irritability,  so  that 
changes  in  their  tone  may  be  graphically  recorded  (If.  v.  Frey,  O.  B. 
Meyer).  After  addition  of  epinephrin  to  the  Ringer's  solution,  a 
distinct  shortening  of  the  strip  of  artery  results. 

This  vasoconstriction  is  especially  well  marked  in  the  arteries 
of  the  splanchnic  system,  but  occurs  also  in  most  of  the  other  vascular 
systems  (Cow).  According  to  Langendorff,  the  coronary  vessels  are 
exceptional  in  their  behavior,  in  that  in  them  epinephrin,  instead  of 
causing  an  increase  in  the  tone,  causes  a  diminution,  as  shown  by  the 
lengthening  of  the  strip.  In  accordance  with  this,  the  flow  of  the  blood 
through  the  tissues  of  the  surviving  mammalian  heart  is  not  hindered 
but,  on  the  contrary,  is  favored  by  epinephrin. 

Haemostasia — The  use  of  epinephrin  as  a  means  of  causing  local 
anaemia  and  as  a  haemostatic  depends  on  its  power  to  constrict  the 
vessels  lying  at  the  point  of  application.  If  the  drug  be  applied 
(1-1000  or  1-10,000),  in  dilute  solution,  to  mucous  membranes  or 
wounds,  these  become  extremely  pale.  The  anaemia  resulting  from  its 
application  greatly  increases  the  accessibility  of  cavities  lined  by 
mucous  membrane  (for  example,  in  rhinological  practice) .  In  surgery, 
when  it  is  important  to  have  the  operative  field  as  free  from  blood  as 
possible,  epinephrin  may  be  used  locally  to  check  hemorrhage. 

In  Local  Anesthesia. — Mention  has  already  been  made  of  the  great 
advantage  resulting  from  the  addition  of  this  drug  to  the  cocaine 
solutions  employed  in  the  induction  of  local  anaesthesia.  It  is  of  great 
practical  importance  that  the  vasoconstriction  caused  by  epinephrin 
closes  up  the  paths  for  the  absorption  of  the  cocaine,  and  thus  keeps 
this  drug  at  the  place  of  its  application  and  does  not  permit  it  to 
reach  the  central  nervous  system  (see  p.  125).  As  shown  by 
Meltzer  and  Auer  and  also  by  Exner,  epinephrin  delays  absorption 
from  the  peritoneal  cavity.  It  is  also  probable  that  the  absorption 
through  the  lymph-spaces  is  hindered  by  its  actions. 

Effects  on  Distribution  of  the  Blood. — "When  epinephrin  is  injected 
directly  into  the  circulation,  the  visceral  vessels  are  especially  con- 
stricted. Plethysmographic  investigation  shows  a  marked  diminution 
in  the  volume  of  the  intestines,  kidney,  and  spleen,  so  that,  in  spite  of 
the  tremendous  rise  in  blood-pressure,  the  curves  from  these  organs 
move  in  an  opposite  direction  from  the  blood-pressure  curves  (Fig. 
30).  The  blood  is  forced  out  of  the  abdominal  viscera  into  the  heart 
and  lungs,  the  vessels  of  which  are  much  less  affected  than  those  of  the 
other  organs  (Gerhardt). 


EPINEPHRIN 


281 


The  effects,  on  the  Hood-pressure  may  be  obtained  in  their  full 
development  by  the  intravenous  injection  of  a  dose  corresponding  to 
1/100  ing.  per  kilo.  With  subcutaneous  injections  doses  more  than 
one  hundred  times  as  large  are  necessary.  [The  translator  has  found 
that  from  0.6  to  1.0  mg.  injected  intramuscularly  usually  caused  dis- 
tinct effects  in  adult  human  beings,  such  as  a  rise  of  from  10  to  15  mm. 
Hg  and  an  acceleration  of  the  pulse,  with  apparent  increase  in  the 
strength  of  the  cardiac  contractions.  In  two  patients  (out  of  a  series 
of  30  cases)  such  doses  caused  tremendous  pressor  and  other  effects, 
the  symptoms  in  one  case  being  very  alarming.  The  unusual  effects 
were  apparently  due  to  individual  idiosyncrasy,  for  these  two  cases 
reacted  proportionately  to  smaller  doses  given  subsequently.  The 
translator  knows  of  no  adequate  explanation  for  the  difference  in  reac- 
tion to  this  drug  which  the  laboratory  animals  and  man  present,  but 
believes  it  important  to  warn  against  possible  harm  which  might 
result  from  disregarding  it] 


Volume  of 
idney 


Right  front 
leg 

Left  front 
leg 


Flo.  30. — Effect  produced  by  suprarenal  extracts  on  the  blood-pressure  and  on  the  volume  of 
different  organs  {Oliver  and  Schaefer). 

Causes  of  the  Evanescence  of  the  Pressor  Effect. — The  rise  in 
blood-pressure  following  intravenous  administration  seldom  lasts  more 
than  1-3  minutes.  This  difference  between  the  striking  effects  pro- 
duced by  intravenous  injection  and  the  comparatively  slight  effects 
of  subcutaneous  injections  is  doubtless  in  part  due  to  the  great  insta- 
bility of  this  drug,  which  is  decomposed  even  by  weak  soda  solutions. 
[Further,  the  local  vasoconstriction  must  permit  only  a  gradual  en- 
trance of  the  drug  in  the  general  circulation.  This  would  result  in  a 
lessened  intensity  and  a  greater  persistence  of  the  effects  of  the  drug 
when  administered  subcutaneously  (Miller,  Halsey). — TR.]  The 
rapidity  with  which  the  effects  of  the  intravenous  injections  pass  off 
may  be  assumed  to  be  due  in  part  to  a  rapid  oxidation  of  epinephrin 
in  the  alkaline  medium  of  the  body  fluids  and  tissues.  In  addition 
it  is  assumed  that  this  drug  acts  only  at  the  moment  of  entrance  into 
le  nerve-endings  [?]  by  a  "permeation  pressure."  If  this  assump- 


282  PHARMACOLOGY  OF  CIRCULATION 

tion  is  correct,  the  manner  in  which  epinephrin  produces  its  effects 
would  be  analogous  to  that  in  which  muscarine  (p.  248)  acts  (Straub). 

Elimination. — Even  when  large  amounts  of  epinephrin  are  ad- 
ministered subcutaneously  or  administered  by  mouth,  only  minimal 
amounts  are  excreted  in  the  urine  (v.  Fiirth). 

Other  Actions. — Epinephrin  possesses  a  number  of  other  pharma- 
cological actions  in  addition  to  this  effect  on  the  vessels,  which  is, 
for  practical  purposes,  its  most  important  action.  One  of  these  is 
the  acceleration  and  strengthening  of  the  heart-beat,  as  a  result  of 
stimulation  of  the  accelerator  nerves.  The  slowing  of  the  pulse 
observed  at  the  commencement  of  the  rise  in  blood-pressure  is  the 
result  of  stimulation  of  the  vagus  centre  by  the  increased  blood- 
pressure  (see  p.  245) .  The  respiration  during  the  period  of  high  blood- 
pressure  is  affected  in  a  peculiar  manner,  temporary  cessation  alter- 
nating with  periods  of  deeper  and  more  rapid  breathing. 

Epinephrin  causes  mydriasis  by  stimulation  of  the  dilator  pupillae,  analogous 
to  that  caused  by  stimulation  of  the  sympathetic  in  the  neck  ( p.  159 ) .  It  causes 
increased  secretion  of  the  salivary  glands  (Langley),  as  also  of  the  glands  of  the 
skin  of  the  frog  (Ehrmann),  and  atropine  does  not  stop  these  secretions  when 
thus  excited.  Further,  epinephrin,  even  in  small  doses,  is  a  powerful  excitant  of 
the  contractions  of  the  uterus  (pp.  222,  229),  but,  on  the  other  hand,  intestinal 
peristalsis  is  inhibited  by  it  (p.  173).  The  epinephrin  glycosuria  (Blum,  Herter 
and  Wakeman)  results  from  the  stimulating  effect  on  the  transformation  of  gly- 
cogen  in  the  liver.  Glycosuria  produced  by  brain  puncture  and  many  toxic  gly- 
cosurias  are  to  be  considered  as  resulting  from  a  suddenly  increased  secretion  of 
•epinephrin  (p.  419). 

It  is  probable  that  the  arteriosclerotic  changes  found  in  the  aorta  of  animals 
which  have  for  some  time  been  treated  with  epinephrin  (Josue,  W.  Erb)  are 
not  the  result  of  the  effect  on  the  blood-pressure,  but  are  due  to  a  special  toxic 
action  such  as  is  exerted  by  other  substances  of  quite  different  nature  (Heubner). 

Seat  of  Action. — The  question  as  to  which  elements  of  the  vessel 
wall  are  affected  by  the  vasoconstricting  action  of  epinephrin  may  be 
discussed  only  in  connection  with  the  other  actions  of  the  drug.  In 
this  connection  it  was  first  shown  by  Wessely  for  the  eye,  and  later 
by  Langley  and  Elliot  for  all  other  vegetative  organs,-  that  in  all  of 
them  epinephrin  produced  the  same  effects  as  are  produced  by  stimu- 
lation of  their  sympathetic  nerves,  but  never  the  same  as  those  caused 
by  stimulation  of  the  other  vegetative  nerves.  This  striking  paral- 
lelism renders  it  highly  improbable  that  the  action  of  this  drug  on 
the  smooth  muscles  of  the  vessel  walls  and  of  the  dilator  pupillaB,  etc., 
is  a  direct  one  on  the  muscles.  It  appears  much  simpler  to  attribute 
this  action  to  the  stimulation  of  the  nerve-endings  of  the  sympathetic 
system.  A  very  important  aid  in  the  solution  of  this  matter  has  been 
furnished  by  the  above-mentioned  experiments  of  Langendorff  on  the 
coronary  vessels,  which  are  not  constricted  by  epinephrin  but  are 
dilated.  According  to  the  studies  of  Maass,  moreover,  vasodilators 
for  the  coronary  vessels  actually  pass  down  in  the  accelerator  nerve, 
while  the  vasoconstrictors  lie  in  the  vagus  trunk.  This  anatomical 
fact,  in  conjunction  with  the  action  of  epinephrin  on  the  coronary  ves- 


EPINEPHRIN  283 

sels,  serves  as  another  support  of  the  hypothesis  that  epinephrin  acts 
on  the  sympathetic  nerve-endings  and  not  on  the  muscles  in  the  vessels, 
for  we  have  no  reason  to  believe  that  the  muscles  of  the  coronary 
vessels  differ  essentially  from  those  of  other  vessels. 

The  point  at  which  epinephrin  acts,  however,  cannot  be  those  nervous  struc- 
tures which  degenerate  after  section  of  the  nerve-trunks,  for  Langley  found  that 
epinephrin  was  still  effective  at  a  time  when  as  a  result  of  section  of  the  nerve- 
trunk  all  the  histologically  differentiable  nerve-endings  had  undergone  degenera- 
tion. He,  therefore,  locates  the  action  of  epinephrin  in  a  receptive  intermediary 
substance  lying  between  the  nerve  and  the  muscle.  Inasmuch  as  we  look  upon  the 
connection  between  the  nerve  and  the  muscle  as  an  exceedingly  intimate  one,  and 
we  possess  no  criterion  for  determining  what  belongs  to  the  nerve  and  what  does 
not,  this  hypothetical  receptive  intermediary  substance  must  be  considered  as  a 
part  of  the  nerve-ending. 

Physiological  Tests  for  Epinephrin. — The  physiological  importance 
of  epinephrin  has  been  established  ever  since  it  was  proved  that  nor- 
mal blood-serum  contained  it.  Although  the  exceedingly  small  amount 
of  epinephrin  normally  present  in  the  blood  cannot  be  demonstrated  by 
chemical  methods,  it  is  possible  to  show  that  serum  exerts  the  charac- 
teristic physiological  effects  of  epinephrin,  and  especially  is  this  clear 
with  the  serum  of  blood  obtained  from  the  suprarenal  veins.  This 
was  first  incontestably  demonstrated  by  Ehrmann,  who  found  that 
serum  obtained  from  the  suprarenal  veins  exerted  the  same  mydriatic 
action  as  epinephrin  when  it  was  applied  to  the  enucleated  frog's  eye. 
0.  B.  Meyer  and  Schlayer  found  that  blood-serum  causes  the  same 
contraction  of  smooth  muscles  of  the  surviving  artery  as  is  caused  by 
extremely  dilute  solutions  of  epinephrin.  In  the  same  fashion  normal 
blood-serum  causes  an  increase  in  the  tone  of  a  rabbit's  uterus  "sur- 
viving" in  Ringer's  solution,  which  is  an  extremely  delicate  object  for 
testing  epinephrin  (Frdnkel),  and  Trendelenburg  found  that,  when 
the  blood-vessels  of  the  frog  were  perfused  with  serum,  the  retardation 
of  the  flow  was  identical  in  every  respect  with  that  observed  when 
very  dilute  solutions  of  epinephrin  were  perfused. 

While  O'Connor  has  shown  that  other  active  substances  contained 
in  the  serum  are  responsible  for  part  of  this  effect,  the  greater  activity 
of  serum  obtained  from  the  suprarenal  veins  as  compared  with  that 

tained  from  other  organs  indicates  that  these  physiological  reactions 

the  normal  serum  are  at  least  in  part  due  to  epinephrin.  Thus,  the 
hrmann-Meltzer  pupil  reaction  is  strongly  positive  only  when  the 
Turn  from  the  suprarenal  veins  is  used,  and  is  not  ordinarily  pro- 

ced  by  the  serum  from  the  carotid  or  jugular.  In  this  fashion  it 
demonstrated  that  the  blood  from  the  suprarenal  veins  actually 
ontained  more  epinephrin  than  any  other  blood  (Ehrmann}.  Simi- 
larly such  serum  constricts  the  vessels  of  the  frog  much  more  strongly 
than  does  serum  from  carotid  (O'Connor)  (see  Fig.  31).  Moreover, 
blood  from  the  suprarenal  vein  when  injected  into  a  second  animal 
produces  a  greater  rise  of  blood-pressure  than  blood  obtained  from 
other  vessels  (Szymonovicz,  Camus  et  Langlois).  The  strongest  evi- 


284 


PHARMACOLOGY  OF  CIRCULATION 


dence  of  a  physiological  secretion  of  epinephrin  is  the  histological  fact, 
observed  by  Arnold,  that  the  granular  chromaffin  bodies,  found  in  the 
medullary  cells  of  the  suprarenal  gland,  pass  directly  from  these  cells 
into  the  first  beginnings  of  the  suprarenal  veins. 

Fig.  31  shows  the  course  of  the  vasoconstriction  produced  in  the 
surviving  frog's  vessels  by  serum  from  the  carotid  and  by  that  from 
the  suprarenal  veins.  That  the  stronger  vasoconstricting  effect  of  this 
last-mentioned  serum  is  actually  due  to  the  presence  of  epinephrin, 
which  has  been  secreted  into  these  veins,  is  indicated  by  the  destruction 
of  the  active  substance  if  oxygen  be  passed  through  the  serum  for  a 
number  of  hours,  this  ready  oxidizability  being  characteristic  of 
epinephrin. 

Physiological  Significance  for  the  Blood-pressure. — According  to 
Tscheboksaroff,  Asher,  and  Kahn,  it  would  appear  that  the  functional 
activity  of  the  splanchnic  nerve  depends  on  the  internal  secretion  of 
the  suprarenal  glands.  Bilateral  extirpation  of  these  glands  is  fol- 


om  adrenal  teins 


it  for  6  hovrt 


40 


lowed  by  general  prostration  with  a  pronounced  fall  in  the  body  tem- 
perature and  progressive  sinking  of  the  blood-pressure,  and  is  fol- 
lowed by  death  unless  accessory  suprarenals  are  present,  or  unless 
a  sufficiently  long  period  of  time  has  elapsed  between  the  extirpation  of 
the  first  and  second  gland,  to  permit  of  a  compensatory  hypertrophy 
of  the  chromaffin  tissue  in  other  parts  of  the  body  (Brown-Sequard, 
Langlois,  Szymonovicz,  Hultgren  u.  Anderson,  Strehl  u.  Weiss). 
However,  it  has  been  shown  by  Biedl  that  the  importance  of  the 
suprarenals  for  the  maintenance  of  life  is  not  entirely  dependent 
on  the  secretion  of  epinephrin,  for  the  cortex  of  the  gland  also 
possesses  vitally  important  functions,  which  perhaps  consist  in  render- 
ing harmless  the  poisonous  products  of  muscular  activity  (Langlois 
et  Abelous).  The  great  physiological  importance  of  the  suprarenals 
is  also  evidenced  by  the  uncommonly  rich  blood  supply  of  these  tiny 
organs  (Langlois,  Flint) . 

From  what  has  already  been  said,  there  can  be  no  doubt  that 
epinephrin  aids  in  maintaining  and  regulating  the  normal  peripheral 


EPINEPHRIN  285 

vascular  tone.  It  would  appear  that  a  certain  apparently  constant 
amount  of  epinephrin  is  present  in  the  blood,  and  that,  as  there  is  a 
continuous  inflow  of  this  substance  into  the  blood,  a  constant  effect 
on  the  sympathetic  nerve-endings  is  exerted,  the  epinephrin  which 
has  reached  the  cells  being  constantly  destroyed,  but  that  just  entering 
them  stimulating  the  nerve-endings  (Straub  u.  Kretschmer) .  Inas- 
much as  the  histological  studies  of  Wiesel  have  shown  that  the  medulla 
of  the  suprarenal  gland  and  the  other  chromaffin  tissues  stand  in  a 
close  developmental  relation  to  the  sympathetic  system,  it  would 
appear  that  this  system  provides  for  the  maintenance  of  its  own  stimu- 
lation by  itself  producing  the  stimulating  substance. 

Practical  Applications. — The  use  of  epinephrin  to  influence  the 
cardiac  action  and  the  general  distribution  of  the  blood  will  be  dis- 
cussed later.  It  is  extensively  employed  as  a  local  application  to 
mucous  membranes  and  bleeding  wounds,  especially  in  combination 
with  cocaine,  which  also  has,  to  a  less  degree,  a  vasoconstricting  effect 
(seep.  124). 

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286  PHARMACOLOGY  OF  CIRCULATION 

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THE  DIGITALIS  BODIES  are  also  to  be  numbered  among  the  substances 
which  cause  constriction  in  important  vascular  systems  by  a  local 
action.  With  them,  too,  this  action  is  a  local  one  in  the  vessel  wall, 
for  the  vasoconstriction  produced  by  them  occurs  after  section  of  the 
cervical  cord  and  pithing  of  its  lower  portions.  Here,  too,  it  is  not 
possible  to  determine  definitely  which  elements  in  the  vessel  wall  are 
acted  upon,  but  it  appears  justifiable  to  consider  the  action  on  the 
vessels  as  analogous  to  that  011  the  heart,  which,  in  point  of  fact,  is 
only  a  more  highly  specialized  artery.  That  the  action  of  digitalis 
on  the  vessel  walls  is  a  local  one,  taking  place  in  the  vessel  walls 
themselves,  was  indicated  by  the  first  observations  made  by  perfusing 
cold-  and  warm-blooded  organs  (Donaldson  and  Stevens,  Ko~bert)  with 
digitalis  substances,  for  in  these  experiments  the  blood  stream  was 
retarded  after  addition  of  such  drugs  to  the  perfusion  fluid.  As 
long  as  such  evidence  depended  only  on  experiments  on  surviving 
organs,  it  remained  questionable  whether  the  same  held  good  for  living 
animals.  Since  that  time  the  vasoconstricting  action  in  the  intact 
mammal  has  been  definitely  proved  by  the  use  of  various  experimental 
methods. 

In  an  indirect  fashion  Lauder-Brunton  and  Tunnicliffe  reached  the  conclusion 
that  the  vessels  were  constricted  by  observing  the  retarded  flow  of  blood  through 
the  narrowed  arterioles  into  the  veins.  If  the  heart  in  the  intact  circulation 
be  stopped  by  stimulation  of  the  vagus,  the  rapidity  and  the  extent  of  the 
fall  in  pressure  in  the  aorta  depend  on  the  resistance  in  the  vessels  against  which 
the  large  arteries  empty  themselves  during  the  persistent  diastole  of  the  heart, 
and  if  the  blood  path  is  widely  opened  the  outflow  is  rapid  and  the  blood-pressure 
sinks  rapidly.  With  contracted  vessels,  on  the  contrary,  this  must  take  place 
more  slowly.  In  the  experiments  of  these  authors  comparison  of  the  behavior 
of  the  blood-pressure  during  the  stoppage  of  the  heart  induced  by  vagus  stimu- 
lation showed  an  appreciably  slower  fall  after  injection  of  digitalis  than  occurred 
before. 

Differences  in  the  Degree  of  Vasoconstriction  Induced  in  Different 
Organs. — A  knowledge  of  the  behavior  of  the  different  vascular  sys- 
tems under  the  influence  of  digitalis  has  been  obtained  by  means  of  the 


DIGITALIS  AND  THE  VESSELS 

plethysmograph,  as  well  as  by  the  method  of  measuring  the  amount 
of  blood  passing  through  the  separate  vascular  systems  as  described 
on  page  242  (Bradford  and  Phillips,  F.  Pick}.  In  these  experiments 
it  was  demonstrated  that  after  very  small  doses  the  vasoconstriction 
affects  chiefly  the  visceral  vessels  (Gottlieb  u.  Magnus),  while  other 
vascular  systems — for  example,  the  vessels  of  the  skin  and  muscles, 
as  also  the  renal  vessels — dilate  (Loewi  u.  Jonescu}.  This  difference 
in  behavior  is  due  to  a  quantitatively  different  susceptibility  of  the 
different  vascular  systems,  which  may  best  be  demonstrated  in  per* 
fusion  experiments  on  surviving  organs.  Those  concentrations  of 
digitoxin  and  strophanthin,  which  when  perfused  dilate  the  renal 
vessels,  cause  a  constriction  of  the  intestinal  vessels,  while  the  vessels 
of  the  skin  and  muscles  are  entirely  uninfluenced  and  are  constricted 


Leg 


iwwiiwnfl!^^ 

FIG.  32. — Effects  of  strophanthin  on  blood-pressure  and  on  volume  of  spleen  and  leg. 

only  by  much  higher  concentrations  (Kasztan,  Fahrenkamp).  It  may 
be  concluded  that  in  the  living  animal  the  vessels  of  the  extremities 
will  be  dilated  during  the  early  stages  of  digitalis  action,  because 
the  blood  will  be  mechanically  driven  out  of  the  visceral  vessels  when 
these  are  constricted  while  the  vessels  in  the  extremities  are  as  yet 
uninfluenced  by  the  drug.  All  these  vasomotor  reactions  are  in  part 
caused  by  depressor  reflexes,  which  cause  a  distinct  dilatation  of  the 
vessels  in  the  extremities  in  order  that  in  them  a  place  may  be  found 
for  the  blood  forced  out  from  the  visceral  vessels  (see  Fig.  32) . 

The  behavior  of  the  kidney  vessels  previously  mentioned  demon- 
strates that  digitalis  bodies  may  exert  a  vasodilating  action  which, 
as  shown  by  Loewi  and  Jonescu1 's  experiments  on  the  kidney  isolated 
from  its  nerves  and  by  Kasztan' s  and  Fahrenkamp's  on  surviving- 
organs,  is  a  direct  one  on  the  vessel  walls.  In  the  vessels  of  the  intes- 


288  PHARMACOLOGY  OF  CIRCULATION 

tine  almost  the  only  action  of  the  digitalis  bodies  is  that  of  vasocon- 
striction. 

Quantitative  Differences  between  the  Different  Digitalis  Bodies. — 
All  the  members  of  the  digitalis  group  have  a  vasoconstricting  action, 
which,  however,  is  developed  to  a  different  degree  in  different  members 
of  the  group,  being  developed  in  the  case  of  digitoxin  and  much 
less  so  in  digitalin,  strophanthin,  and  others. 

After  toxic  doses  of  these  substances,  but  especially  of  digitoxin, 
all  parts  of  the  systemic  circulation  take  place  in  the  vasoconstriction, 
and  the  dilatation  of  the  peripheral  systems  does  not  occur — or  is 
developed  only  as  the  action  passes  off  and  the  blood-pressure  rises 
markedly.  With  doses  causing  a  somewhat  less  intense  effect,  the 
intestinal  and  hepatic  vessels  and  usually  also  the  renal  vessels  are 
constricted,  while  in  the  periphery  of  the  body,  as  well  as  in  the 
brain,  the  blood  flow  is  improved. 

Finally,  very  small  doses  produce  only  a  change  in  the  distribution 
of  the  blood  without  rise  in  the  general  pressure,  the  intestinal  vessels 
being  constricted  and  the  renal  vessels  being  dilated  (Loewi  and 
Jonescu). 

BIBLIOGRAPHY 

Bradford  and  Phillips:  Journ.  of  Physiol.,  1887,  vol.  8,  p.  117. 

Donaldson  and  Stevens:  Journ.  of  Physiol.,  1883,  vol.  4,  p.  165. 

Fahrenkamp :   Arch.  f.  exp.  Path.  u.  Pharm.,   1911. 

Gottlieb  u.  Magnus:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  47. 

Kasztan:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  406. 

Kobert:  Arch.  f.  exp.  Path.  u.  Pharm.,  1886,  vol.  22. 

Lauder-Brunton  and  Tunnicliffe:  Jour,  of  Physiol.,  1896,  vol.  20,  p.  354. 

Loewi  u.  Jonescu :  Arch,  f .  exp.  Path.  u.  Pharm.,  1908,  vol.  59. 

Pick,  F.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42. 

PERIPHERALLY  ACTING  VASCULAR  DEPRESSANTS 

AMYL  NITRITE. — Numerous  drugs  and  poisons  possess  a  depressing 
action  on  the  vessel  walls.  In  particular,  amyl  nitrite  and  other 
nitrites,  in  addition  to  acting  on  the  vasomotor  centres,  cause,  even  in 
non-poisonous  dosage,  a  demonstrable  peripheral  vascular  paralysis. 

THE  NARCOTICS  OF  THE  ALCOHOL  group,  especially  chloroform  and 
chloral  hydrate,  show  a  similar  peripheral  action  only  in  such  high 
concentration  that  it  is  of  significance  only  in  most  severe  poisoning. 
This  effect  is  shown  in  surviving  organs  by  the  great  increase  in  the 
blood  flow  when  these  drugs  are  perfused.  In  perfusion  experiments 
an  effect  on  the  vessels  occurs  only  with  a  chloroform  content  of  0.1 
per  cent.  (Sherrington  and  Sowton),  and,  as  a  concentration  of  from 
0.06-0.07  per  cent,  of  chloroform  quickly  kills  by  paralysis  of  the 
respiration,  this  peripherally  induced  dilatation  in  contradistinction 
to  the  central  vasomotor  paralysis  is  of  no  practical  significance  for 
the  action  of  chloroform. 

CAPILLARY  DILATORS. — It  is  probable  that  toxic  actions  on  the 
vessel  walls  are  often  not  limited  to  the  arterioles,  but  that  the  calibre 


PERIPHERAL  VASODILATORS  289 

of  the  capillaries  may  also  be  affected.  This  has  been  demonstrated 
for  the  vasodilating  action  of  arsenic  and  antimony,  as  well  as  for 
other  metal  salts  and  other  substances,  among  which  is  sepsin,  a  very 
poisonous  base  produced  by  certain  bacteria.  The  point  of  predilective 
action  of  these  capillary  poisons  lies  in  the  walls  of  the  intestinal 
vessels.  That  this  vasodilatation  is  of  peripheral  origin  is  demon- 
strated by  the  fact  that  the  excitability  of  the  splanchnic  nerve  for 
electric  stimuli  constantly  diminishes  as  the  fall  in  blood-pressure 
progresses  (Bohm  u.  Unterbringer,  Pistorius).  The  extreme 
hyperaemia  of  the  intestines  resulting  from  these  toxic  actions,  the 
extravasations  of  blood,  and  the  alterations  in  the  capillary  walls 
make  it  clear  that  these  poisons  exert  an  elective  action  on  the  capil- 
laries. 

The  elective  action  which  some  drugs  exert  on  special  vascular  sys- 
tems is  the  basis  of  their  therapeutic  application. 

YOHIMBIN  is  a  good  example  of  a  drug  exerting  such  a  peripheral 
elective  action  on  vessels,  which  occurs  even  after  previous  section 
of  the  nerves,  but  affects  only  certain  vascular  systems,  or  at  least 
is  especially  pronounced  in  them.  It  causes  a  dilatation  of  the  vessels 
in  the  genital  organs,  which  may  be  demonstrated  by  the  increased 
flow  of  blood  through  the  dorsal  vein  of  the  penis.  Simultaneously 
the  vascular  systems  of  the  skin  and  kidney  dilate,  while  other  vessels 
—for  example,  those  of  the  spleen — contract.  The  aphrodisiac  action 
of  yohimbin  (p.  219)  is  due  partly  to  this  increased  blood  flow  to  the 
genital  organs,  and  partly  to  an  augmentation  of  the  reflex  excitability 
of  the  centres  of  erection  (Franz  Muller). 

CAFFEINE  also  exerts  a  local  elective  action  on  the  renal  and  the 
cerebral  vessels,  while  the  dimethylxanthines  ^theobromine,  theocin, 
etc.),  as  well  as  digitalis,  act  in  a  like  manner  on  the  renal  vessels. 
Caffeine  and  theobromine,  and  perhaps  also  amyl  nitrite,  have  a 
specific  power  of  dilating  the  coronary  vessels,  an  action  of  great  sig- 
nificance for  the  flow  of  blood  through  the  tissues  of  the  heart. 

VASCULAR  ALTERATIONS  FROM  LOCAL  APPLICATIONS. — Aside  from 
such  elective  pharmacological  actions  in  the  different  vascular  systems, 
local  vasodilatations  and  vasoconstrictions,  resulting  from  a  direct 
contact  of  chemical  substances  with  the  vessel  walls,  are  of  considerable 

portance.    Thus,  the  astringents  (see  p.  213),  when  not  too  highly 
ncentrated,  produce  a  constricting  effect  on  the  vessels  at  the  place 

application.    The  same  substances  in  higher  concentrations,  as  well 

all  irritants,  dilate  the  blood-vessels  locally.     Further,  in  inflam- 

tion,  local  vasodilatation  may  be  caused  either  by  irritating  sub- 
ces  penetrating  from  the  exterior  or  by  products  of  the  pathologi- 
cal tissue  changes.    The  influence  of  increased  function  is  of  a  similar 
nature,  for  there  is  certainly  a  local  cause  for  the  increased  inflow 
of  blood  which  occurs  during  activity  of  an  organ,  caused  probably 
by  some  of  the  products  of  the  metabolism  of  the  organ  exerting  a 
19 


290  PHARMACOLOGY  OF  CIRCULATION 

vasodilatating  action.  It  may  be  that  the  vasodilatation,  which  Bier 
has  shown  to  result  from  temporarily  cutting  off  the  blood  supply, 
is  brought  about  in  an  analogous  fashion.  Finally,  in  this  connection, 
it  is  proper  to  state  that  cold  constricts  while  heat  dilates  the  vessels. 

BIBLIOGRAPHY 

Bb'hm  u.  Unterberger :  Arch.  f.  exp.  Path.  u.  Pharm.,  1874,  vol.  2,  p.  89. 
Heubner:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56,  p.  370. 
Muller,  Franz:  Arch.  int.  de  Pharmacodyn.  et  de  Ther.,  1907,  vol.  17,  p.  81. 
Pistorius:    Arch.  f.  exp.  Path.  u.  Pharm.,  1883,  vol.  16,  p.  188. 
Sherrington  and  Sowton:  Labor.  Report.,  1903,  vol.  5,  Univ.  Liverpool. 
Sherrington  and  Sowton:  Brit.  Medic.  Journ.,  1904,  vol.  2,  p.  162. 

THE  EFFECTS  ON  THE  CIRCULATION  AS  A  WHOLE  PRODUCED 
BY  DRUGS  ACTING  ON  THE  HEART  AND  ON  THE  VESSELS 

The  indications  for  the  administration  of  drugs  acting  on  the 
circulation  are  found  in  the  presence  of  disturbances  of  the  heart 
function  or  of  alterations  in  the  distribution  of  the  blood,  resulting 
from  vascular  paresis  or  vascular  cramp. 

DISTURBANCES  OF  THE  CARDIAC  FUNCTION. — The  heart,  as  the  motor 
organ  of  the  circulation,  has  the  task  of  driving  the  blood  through 
the  arterial  and  venous  portions  of  the  systemic  and  pulmonary  circu- 
lations in  quantities  sufficient  to  supply  the  needs  of  all  the  organs. 
It  is  not  able  to  do  this — 1st,  if  it  is  beating  too  slowly;  2d,  if  both 
ventricles  empty  themselves  too  incompletely ;  or,  3d,  if  either  of  the 
two  ventricles  is  no  longer  contracting  forcibly  enough  to  expel  its 
contents  in  a  normal  fashion.  These  different  types  of  insufficient 
heart  function  lead  necessarily  to  somewhat  different  results,  for  in 
case  of  too  slow  action  of  both  halves  of  the  heart,  or  in  case  of  an 
equally  incomplete  emptying  of  both  ventricles,  there  will  result  only 
a  dangerous  retardation  of  the  blood  flow  in  both  circulations.  On 
the  other  hand,  in  case  one  ventricle  is  unable  to  empty  itself  com- 
pletely, the  distribution  of  the  blood  throughout  the  body  will  become 
abnormal  and  stasis  will  result. 

In  an  acute  ancemia  from  hemorrhage  both  sides  of  the  heart  re- 
ceive and  pump  out  too  small  a  quantity  of  blood.  Also  in  enfeebled 
conditions  of  the  heart,  such  as  may  be  caused  by  numerous  exogenous 
poisons,  as  well  as  by  the  toxins  of  infection,  the  contractions  of  both 
ventricles  become  equally  incomplete  and  feeble.  In  both  cases  the 
skin  becomes  pale  and  the  extremities  cold  and  the  brain  is  poorly 
supplied  with  blood.  As  this  organ  is  extremely  sensitive  to  dis- 
turbances of  its  circulation,  interference  with  its  blood  supply  quickly 
results  in  a  feeling  of  f aintness.  While  the  other  organs  also  suffer 
more  or  less  as  a  result  of  the  retardation  of  the  blood  flow,  the  heart 
especially  suffers  on  account  of  the  insufficient  circulation  in  the 
coronary  vessels. 

Stasis. — When  one  ventricle  is  beating  feebly  while  the  other 
continues  to  function  normally,  or  when  the  efficiency  of  one  is  im- 


THEORY  OF  DIGITALIS  ACTION  291 

paired  to  a  greater  degree  than  that  of  the  other,  quite  different  con- 
ditions arise.  If,  for  example,  the  left  ventricle  contracts  incompletely, 
on  the  one  side,  too  little  blood  flows  into  the  aorta  and,  on  the  other, 
the  auricle  is  unable  to  empty  itself  completely  into  the  ventricle  on 
account  of  the  residual  blood  left  there  at  the  end  of  the  incomplete 
systole.  The  blood,  therefore,  accumulates  first  in  the  left  auricle 
and  then  in  the  pulmonary  vessels.  If,  now,  the  right  heart  continues 
to  pump  out  blood  in  the  same  amounts  as  before,  the  left  heart  must 
soon  become  dilated  and  the  stasis  in  the  pulmonary  vessels  will  in- 
crease, dyspnoea  and,  with  marked  stasis,  oedema  of  the  lungs  resulting. 

If  it  be  the  right  ventricle  which  is  affected,  the  blood  accumulates 
in  the  right  auricle  and  the  great  veins,  and  especially  in  the  capil- 
laries of  the  whole  portal  system,  which  is  immediately  affected  by 
every  rise  in  pressure  in  the  vena  cava.  Congestion  of  the  liver, 
impaired  renal  circulation  with  its  resulting  oliguria,  and  stasis  in  the 
vessels  of  the  intestines  result,  and  ascites  may  develop. 

Effects  on  the  General  Blood  Flow. — With  one  of  the  ventricles 
contracting  inefficiently,  the  arterial  portion  of  its  vascular  system  is 
inefficiently  filled,  and  the  blood  accumulates  and  remains  in  the 
veins  from  which  it  receives  its  supply.  This  blood  is,  as  it  were, 
removed  from  the  circulation,  so  that  the  blood  flow  in  all  the  tissues 
is  diminished.  With  marked  venous  stasis  the  capillaries  are  also 
overfilled.  Cyanosis  results  when  too  little  blood  flows  through  the 
lungs. 

Circulatory  Insufficiency  Due  to  Cardiac  Disease. — Such  conditions 
arise  both  in  disease  of  the  myocardium  and  of  the  valves,  unless  the 
resulting  interference  with  the  circulation  of  the  blood  is  more  or 
less  completely  compensated.  The  first  compensatory  change,  is 
brought  about  by  hypertrophy  of  the  muscles  of  the  overfilled  and 
weakly  contracting  part  of  the  heart  or  of  the  heart  chamber  next 
involved,  which  is  thus  enabled  to  pump  out  the  blood  in  sufficient 
amounts  and  with  sufficient  force  to  overcome  any  unfavorable  con- 
ditions in  the  circulation.  When,  as  a  result  of  progressive  valvular 
or  myocardial  disease  or  of  impaired  nutrition  of  an  overtaxed  heart, 
»mpensation  is  finally  broken  down,  stasis  develops  in  the  pulmonary 

systemic  systems  or  in  both,  and  its  symptoms — dyspnoea,  cyanosis, 

gestion  of  the  liver,  oliguria,  ascites,  oedema,  etc. — result.  Under 
conditions,  digitalis  is  the*  sovereign  remedy. 


THEORY  OF  THE  ACTION  OF  DIGITALIS 

The  separate  pharmacological  actions  of  digitalis  having  been 
ussed,  it  is  now  in  order  to  consider  the  general  effects  produced  by 
these  separate  actions.  As  stated  in  previous  sections  (see  pp.  264-5), 
the  drugs  of  this  group  enable  the  heart  to  accomplish  more  work 
with  each  contraction,  and  proofs  have  been  presented  (see  p.  286) 
that  thus  the  minute  volume  of  blood  pumped  is,  under  certain  condi- 


292  PHARMACOLOGY  OF  CIRCULATION 

tions,  increased.  It  has  also  been  demonstrated  that,  simultaneously 
with  such  alterations  of  the  heart  function,  vasoconstriction  occurs 
in  various  vascular  systems,  and  that  these  primary  and  direct  digi- 
talis actions  tend  to  bring  about  a  rise  of  blood-pressure.  A  third 
digitalis  action — that  is,  a  retarding  of  the  cardiac  action,  which 
appears  in  the  early  stages — works  in  opposition  to  these  two  blood- 
pressure  raising  actions  (see  p.  245). 

THE  RETARDATION  OF  THE  PULSE  is  one  of  the  first  of  the  digitalis 
effects  to  appear,  and  it  is  so  well  developed  after  therapeutic  doses 
of  the  drug  that  Traube  originally  considered  this  the  most  important 
result  produced  by  therapeutic  doses.  He  also  recognized  it  as  due 
chiefly  to  a  central  stimulation  of  the  vagus,  which  view  is  held  by 
many  at  the  present  day.  Lenz's  and  Traube's  own  later  recognition, 
as  a  result  of  experiments  on  animals,  of  the  great  rise  in  blood- 
pressure  caused  by  effective  doses  led  to  his  abandonment  of  this  view, 
and  he  concluded  that  the  slowing  of  the  heart  action  was  simply 
one  of  the  symptoms  resulting  from  the  general  action  on  the  circu- 
lation, a  symptom,  moreover,  of  considerable  importance,  for  it  sup- 
plies a  convenient  means  for  determining  the  degree  of  digitalis  action 
which  has  been  produced. 

RISE  OF  BLOOD-PRESSURE. — With  the  discovery  of  the  rise  in  blood- 
pressure  which  in  normal  animals  is  caused  by  digitalis,  the  doctrine 
of  digitalis  actions  entered  on  a  new  phase,  and  this  action  has  since 
then  exerted  a  preponderating  influence  on  the  views  of  its  pharmaco- 
logical action.  The  therapeutic  effects  of  the  drug  have  been  attributed 
to  the  improvement  of  the  blood-pressure  and  the  better  filling  of 
the  arteries  resulting  from  its  use,  and  indications  for  its  employment 
have  been  sought  in  conditions  of  low  blood-pressure.  However,  as 
will  soon  be  seen,  modern  clinical  observations  force  an  abandonment 
of  this  view,  so  that  the  explanation  of  its  curative  action  is  to  be 
found  not  so  much  in  a  raising  of  the  blood-pressure  as  in  an  alteration 
of  the  distribution  of  the  blood. 

However,  in  order  properly  to  understand  the  complex  actions  of 
digitalis  and  their  influence  on  the  blood-pressure  and  the  distribution 
of  the  blood  throughout  the  body,  it  is  best  to  start  with  a  considera- 
tion of  the  augmentation  of  blood-pressure  which  in  animals  regularly 
results  from  administration  of  toxic  doses. 

The  increased  "pulse  volume"  of  the  heart  will  of  itself  tend  to 
raise  the  aortic  blood-pressure.  This  has  been  demonstrated  in  the 
most  indisputable  fashion  by  Bock,  who,  making  use  of  his  "heart- 
lung"  circulation,  found  that  after  injections  of  digitalis  bodies  the 
blood-pressure  quickly  rose,  although  at  first  the  heart-rate  was  un- 
changed (see  Fig.  33  and  p.  240) .  Such  results  prove  that  increase  of 
the  pulse  volume  of  the  heart  is,  at  any  rate,  one  of  the  causes  of 
the  increased  blood-pressure. 

The  augmentation  of  the  pulse  volume  caused  by  digitalis  may  be 


THEORY  OF  DIGITALIS  ACTION 


293 


due  to  a  more  extreme  relaxation  of  the  heart  without  any  increase 
of  the  contractions,  or  it  may  be  that  the  ventricle,  which  was  not 
contracting  maximally,  under  the  influence  of  the  drug  is  enabled  to 
contract  more  completely  than  before.  Both  factors  may  work  to- 
gether, but  much  speaks  for  the  view  that  a  more  complete  contrac- 
tion is  the  chief  factor  in  increasing  the  pulse  volume  of  the  heart. 
For  example,  in  Bock's  experiment  "the  rise  in  blood-pressure  was  less 
strongly  pronounced  in  strongly  beating  hearts  and  more  pronounced 
in  feebly  contracting  ones."  Under  normal  conditions,  the  contrac- 
tions of  the  mammalian  heart  are  not  complete, — that  is,  it  does  not 
contract  to  such  a  degree  as  completely  to  obliterate  the  ventricular 
lumen.  Moreover,  as  a  result  of  any  damage  done  to  it  by  such 
manipulations  as  are  involved  in  exposing  the  heart  or  in  the  prepara- 
tion of  the  great  vessels  or  in  similar  procedures,  its  contracting 
powers  are  further  impaired.  Therefore,  at  the  end  of  each  systole 
the  ventricle  retains  a  certain  amount  of  blood.  In  Bock's  experi- 
ments, when  the  contractions  were  relatively  complete,  approximating 


1  min.  after 


4  mint,  after 


FIG.  33. — Blood-pressure  in  "heart-lung"  circulation  before  and  after  digitalis  body. 

the  normal,  the  digitalis  could  improve  the  contractions  to  a  slight 
degree  only.  If,  however,  the  heart  were  beating  poorly  and  the 
contractions  were  abnormally  incomplete,  the  favorable  influence 
exerted  on  the  contractions  was  more  pronounced  and  the  blood- 
pressure  rose  markedly. 

The  "  Langendorff "  isolated  heart  always  contracts  less  completely  than  a 
heart  in  situ,  for  the  amount  of  blood  flowing  through  its  vessels  is  always  far 
smaller  than  that  circulating  through  the  vessels  of  the  heart  in  the  intact 
circulation.  .It  is  probably  for  this  reason  that  digitalis  exerts  such  a  favorable 
influence  on  its  contractions  (Magnus  u.  Sowton). 

Cushny's  observations  on  the  intact  circulation  of  dogs  and  cats 
agree  with  this  conception.  Using  a  cardiometer  (a  plethysmographic 
instrument),  he  estimated  the  amount  of  blood  forced  out  during 
each  systole,  and  found  that  digitalis  caused  a  distinct  increase  of 
the  pulse  volume  of  the  heart,  which,  in  his  experiments,  was  undoubt- 
edly somewhat  weakened.  This  was  graphically  recorded,  and  must 
be  attributed  chiefly  to  an  influence  on  the  extent  of  the  contractions, 
for  the  curve  showed  this  to  be  distinctly  increased  while  the  relaxa- 
tion during  diastole  was  but  slightly  influenced. 


294  PHARMACOLOGY  OF  CIRCULATION 

The  rise  in  blood-pressure  is,  however,  not  only  the  result  of  aug- 
mentation of  pulse  volume  of  the  heart,  but  is  also  in  part  the  result 
of  vasoconstriction. 

Tigerstedt,  by  the  use  of  his  Stromuhr  (current  clock),  determined 
the  amounts  of  blood  pumped  into  the  aorta  during  the  unit  of  time, 
before  and  after  the  administration  of  digitalis,  recording  the  carotid 
pressure  at  the  same  time,  and  found  that,  as  a  rule,  the  ''second 
volume"  of  blood  expelled  by  the  heart  increased  simultaneously  with 
the  rise  in  blood-pressure  which  followed  the  injection  of  digitalis. 
However,  in  some  cases  where  the  pressure  rose  markedly,  the  ' '  second 
volume"  of  the  blood  expelled  was  not  increased,  and  in  all  cases  it 
was  diminished  again  at  a  period  when  the  blood-pressure  was  still 
rising. 

The  analysis  of  the  "pressor"  effect  thus  shows  that  the  influence 
of  "heart  work,"  or  "heart  performance,"  and  the  constriction  of 
the  more  important  vascular  systems  go  hand  in  hand.  As  a  result  of 
the  joint  effect  of  these  two  factors,  the  blood-pressure  would  neces- 
sarily be  raised  under  all  conditions,  were  it  not  for  the  fact  that 
digitalis  and  its  congeners  exert  a  third  fundamental  action  on  the 
circulation,  that  of  pulse  retardation,  which,  in  the  first  stages  of 
the  digitalis  action,  acts  in  opposition  to  the  two  other  actions  of  the 
drug.  In  experiments  on  animals,  the  slowing  of  the  heart  thus  caused 
may  be  so  pronounced  as  to  result  in  a  diminution  in  the  volume  of 
blood  pumped  out  per  minute,  in  spite  of  the  increase  in  the  amount 
pumped  by  each  contraction.  It  may  thus  happen  that  at  first  the 
blood-pressure  does  not  rise  (after  injection  of  digitalis)  so  long  as 
the  heart  rate  is  slowed,  but  it  always  rises  if  the  vagi  be  cut  or  when 
at  a  later  period  the  heart  becomes  insusceptible  to  the  inhibitory 
influence  of  the  vagus. 

REGULATORY  ACTION. — Still  a  fourth  fundamental  action  of  digi- 
talis, the  regulation  of  arrhythmic  cardiac  action,  may  be  demonstrated 
in  both  the  intact  circulation  and  the  artificially  perfused  mammalian 
heart  as  well  as  in  the  "heart-lung"  circulation.  This  action  is 
present,  however,  only  in  the  early  stages,*  and,  as  a  matter  of  fact, 
in  the  later  stages  irregularity  of  the  pulse  occurs  and  is  a  typical 
symptom  of  the 

Toxic  ACTION  of  digitalis,  developing  some  time  before  the  blood- 
pressure,  usually  quite  suddenly,  dropping  to  zero  as  the  heart  dies. 
If  the  complex  fashion  in  which  these  different  pharmacological  actions 
of  digitalis  mutually  affect  each  other  be  considered,  the  course  of  the 

*  [This  sweeping  statement  is  correct  only  in  so  far  as  it  refers  to  experiments 
in  animals  or  in  certain  clinical  conditions.  As  a  matter  of  fact,  in  various 
clinical  conditions,  such  as  auricular  fibrillation  very  often  and  premature 
systolic  arrhythmias  occasionally,  a  decided  improvement  of  the  regularity  of 
the  heart  action  is  an  expression  of  the  full  and  desired  therapeutic  action  of 
digitalis  and  its  congeners  (see  translator's  notes,  pp.  266,  300). — TB.] 


THEORY  OF  DIGITALIS  ACTION 


295 


blood-pressure  curve  (Fig.  34)  may  be  understood.     Two  stages  may 
be  differentiated : 

1.  A  stage  during  which  the  heart  action  is  strengthened  and 
slowed,  which  may  be  called  the  therapeutic  stage,  for  these  early 
actions  are  alone  of  therapeutic  value.    Regulation  of  the  heart  action, 
augmentation  of  the  pulse  volume  of  the  heart,  constriction  of  im- 
portant vascular  systems  with  simultaneous  compensating  dilatations 
in  others,  and  slowing  of  the  pulse,  characterize  this  stage.   The  blood- 
pressure,  depending  on  the  extent  to  which  the  pulse  is  retarded,  may 
rise  slightly  or  remain  constant  [or  may  fall  somewhat. — TR.]. 

2.  A  toxic  stage  in  which  the  blood-pressure,  in  spite  of  persisting 
pulse  retardation,  and  later  during  a  sudden  acceleration,  continues 
to  rise.    In  this  stage  the  vasoconstriction  is  chiefly  responsible  for  the 
rise  in  pressure,  for  the  work  performed  by  the  heart  is  at  this  time 
lessened.     Finally  the  heart  action  becomes  irregular  and  the  blood- 
pressure  falls.* 


Normal 
blood-pressure 


i, 

Digitalis 
action  com- 
mencing 


i  FIG.  34. — Blood-pressure  curves  showing  the  effects  of  digitalis  in  a  dog  (Williamt). 

It  is  thus  seen  that  in  the  first  stage  of  digitalis  action,  the  only 
one  having  a  bearing  on  its  therapeutic  usage,  the  Mood-pressure  is 
not  necessarily  raised.  Obviously  the  conditions  in  the  healthy  man 
are  similar.  Frdnkel  observed  in  healthy  persons,  used  as  test  objects, 
a  rise  in  blood-pressure  only  after  the  compensating  pulse  slowing  had 
)een  prevented  by  administration  of  atropine.  Moreover,  in  patients 
whom  stasis  is  present  the  curative  action  of  digitalis  usually  mani- 
fests itself  without  causing  any  augmentation  of  blood-pressure.  We 
the  establishment  of  this  important  fact  to  the  development  of 
lethods  for  the  bloodless  determination  of  blood-pressure  (see  p.  236), 

[The  irregularity  in  the  heart's  action  at  this  stage  may  be  the  result  either 
more  or  less  complete  heart-block,  or  of  premature  systoles   (due  to  increased 
ritability  of  the  ventricle),  or  to  auricular  fibrillation    (due  to  the  digitalis), 
to  combinations  of  two  or  all  of  these  factors. — TB.] 


296  PHARMACOLOGY  OF  CIRCULATION 

for  by  their  employment  it  has  been  shown  that  digitalis  may  remove 
conditions  of  stasis  without  causing  a  rise  in  pressure  (Sahll,  Lang}. 
This  is  also  the  case  after  intravenous  injection  of  digitalis  or  similar 
drugs  (Frdnkel  u.  Schwartz],  the  observations  made  when  the  drug  is 
thus  administered  being  especially  valuable  because  the  effects  on  the 
circulation  ensue  with  the  same  rapidity  as  in  experiments  on  animals 
and  consequently  may  be  exactly  determined. 

ALTERED  DISTRIBUTION  OF  THE  BLOOD. — Inasmuch  as  digitalis  is 
able  to  remove  conditions  of  stasis  without  necessarily  markedly  in- 
fluencing the  blood-pressure,  the  improvement  of  the  circulatory 
function  cannot  be  attributed  to  an  augmentation  of  the  arterial 
pressure.  The  curative  action  of  these  drugs  under  such  conditions 
should  rather  be  attributed  to  the  fact  that  the  abnormal  distribution 
of  the  blood  and  the  stasis  are  replaced  by  normal  conditions.  In 
order  to  understand  this  more  completely  it  is  necessary  to  observe 

THE  ACTION  OF  DIGITALIS  IN  PATIENTS  SUFFERING  FROM  HEART 
DISEASE. 

While  it  is  true  that  the  pharmacological  actions  of  these  drugs 
are  fundamentally  the  same  in  the  normal  and  pathological  circula- 
tions,* in  the  presence  of  pathologically  altered  function  the  results 
produced  by  these  actions  present  themselves  quite  differently.  It 
must  be  quite  clear  that  the  conditions  obtaining  in  cases  of  cardiac 
insufficiency  are  especially  calculated  to  render  the  very  first  stages 
of  digitalis  cardiac  action  beneficial,  for  here  the  drug  is  acting  not 
on  a  ventricle  beating  with  the  normal  optimal  efficiency  but  on  one 
contracting  inefficiently.  Any  disparity  in  the  performance  of  the 
two  ventricles  will  be  removed  by  improvement  of  the  function  of  that 
portion  of  the  heart  which  is  not  working  well.  As  a  result  the 
venous  stasis  will  be  relieved  by  a  shifting  of  the  blood  from  the  venous 
side  of  the  circulation  over  to  the  arterial  portion. 

Under  pathological  conditions  the  slowing  of  the  pulse  produces  a 
distinctly  more  beneficial  result  on  the  total  performance  of  work  by 
the  heart  than  is  the  case  under  conditions  of  health.  While  in  the 
healthy  heart  digitalis  reduces  the  pulse  below  the  normal,  in  cardiac 
disease,  whenever  it  produces  its  desired  effect,  it  usually  brings  it 
back  to  the  normal.  The  effect  of  such  action  on  the  circulation  is 
entirely  different  in  the  two  conditions,  for,  as  shown  by  the  investi- 
gations of  Frank  and  von  Hofmann,  the  heart  beats  with  maximum 
efficiency  when  beating  at  its  normal  rate.  The  simple  inspection  of 
the  accompanying  diagrammatic  curves,  representing  the  changes  in 
the  ventricular  volume  during  a  cardiac  cycle  (Fig.  35),  demonstrates 
that  much  less  blood  is  expelled  by  heart-beats  following  each  other 
with  abnormal  rapidity  than  is  the  case  when  the  rate  of  the  heart 
action  is  about  normal. 

*  See  translator's  note,  pp.  266,  300. 


THEORY  OF  DIGITALIS  ACTION 


297 


The  ordinates  in  the  figure  represent  volumes,  the  abscissa,  time,  and  the 
highest  point  of  the  curve  corresponds  to  the  most  complete  contraction.  The 
amount  of  blood  expelled  at  each  period  of  the  systole,  or  the  amount  received 
during  the  diastole,  is  represented  by  the  difference  in  height  of  the  ordinates. 
With  a  normal  frequency  of  the  heart  action,  the  new  contraction  of  the  heart 
starts  at  that  point  of  the  volume  curve  A-B  which  corresponds  to  the  maximum 
amount  of  blood  which  may  be  expelled  by  the  ventricle.  During  pathologically 
rapid  heart  action,  on  the  other  hand,  the  diastolic  relaxations  become  incomplete, 
because  at  the  moment  of  the  recurrence  of  a  new  contraction — for  example,  at 
the  height  of  lines  6  and  c — the  heart  has  had  time  for  only  incomplete  relaxation 
when  the  next  contraction  begins. 

A  lessened  frequency  of  the  pulse,  therefore,  permits  of  better 
contraction  of  the  whole  cardiac  cycle  and  of  better  refilling  of  the 
ventricles.  When  beating  at  a  moderate  rate,  the  heart  not  only  per- 
forms more  work  in  the  unit  of  time  than  it  does  when  beating  rapidly, 
but  it  performs  this  work  more  economically,  as  it  can  utilize  its 
energy  more  completely.  • 


FIG.  35. 

The  lessening  of  the  pulse  frequency  acts,  therefore,  in  the  same 
sense  as  the  more  powerful  contraction  of  the  heart.  For  this  reason 
it  would  appear  that  digitalis  should  bring  about  a  rise  in  blood- 
pressure,  especially  in  conditions  of  stasis.  Actually,  however,  in 
cardiac  disease,  blood-pressure  in  the  aorta  is  not  materially  increased 
by  digitalis,  in  spite  of  the  important  increase  of  the  volume  per 
second  which  is  expelled  by  the  heart.  This  must  be  due  to  the 
peculiar  conditions  obtaining  in  the  pathological  circulation.  In  all 
probability  important  vascular  systems  become  more  dilated  than  they 
were  before  the  stasis  was  relieved. 

This  view  agrees  with  all  that  has  been  ascertained  about  the 
havior  of  the  vessels  in  conditions  of  stasis.  In  conditions  of  cardiac 
insufficiency,  as  a  rule,  the  arteries  exhibit  a  tendency  to  become  con- 
stricted, their  stronger  tonus  keeping  the  blood-pressure  high.  The 
cause  of  this  vasoconstriction  has  not  yet  been  fully  cleared  up,  but 
certainly  a  role  is  played  here  by  the  carbonic  acid  which  is  present 
in  abnormal  amounts  in  the  blood.  Moreover,  the  absence  of  the  re- 
flexes which  ordinarily  keep  the  peripheral  resistance  low  when  the 
vascular  system  is  well  filled  must  be  of  importance.  However  that 


298  PHARMACOLOGY  OF  CIRCULATION 

may  be,  in  cardiac  insufficiency  a  sort  of  vascular  cramp  must  be 
assumed  to  be  present  before  the  action  of  digitalis  develops.  As  the 
circulation  in  the  lungs  improves  under  the  influence  of  digitalis,  the 
asphyxia,  and  with  it  the  abnormal  contraction  of  the  vessels,  passes 
off,  and,  as  the  heart  is  now  once  more  filling  the  systemic  arteries 
more  completely,  the  depressor  nerve  again  exerts  its  function  as  a 
safety-valve  and  dilates  the  previously  constricted  vessels.  It  is  thus 
evident  that  under  such  pathological  conditions  digitalis  acts  indirectly 
as  a  vasodilator. 

DOES  DIGITALIS  UNDER  CLINICAL  CONDITIONS  CAUSE  VASOCONSTRIC- 
TION? — As,  on  the  other  hand,  experiments  on  the  normal  animal 
have  shown  that  digitalis  exerts  a  direct  constricting  action  on  the 
vessels,  the  question  arises :  Does  this  occur  after  therapeutic  doses  or 
only  after  the  administration  of  those  larger  toxic  doses  which  produce 
augmentation  of  the  blood-pressure? 

In  animal  experiments,  at  least,  the  vasoconstriction  in  the  portal 
systems  and  the  dilatation  of  the  renal  vessels  do  not  occur  later  than 
those  on  the  heart,  but  at  the  same  time,  and  are  observed  after  doses 
producing  hardly  any  effect  on  the  blood-pressure.  As  perfusion 
of  surviving  organs  permits  of  comparing  the  relative  susceptibility 
of  the  vessels  and  the  heart,  it  has.  been  shown  by  this  method  that 
solutions  of  digitalis  and  of  strophanthin,  which  may  be  perfused  for 
a  long  time  through  the  heart  without  harming  it,  promptly  constrict 
the  intestinal  vessels  and  at  the  same  time  dilate  the  renal  arteries 
(Fahrenkamp) .  In  these  experiments  the  effects  on  the  vessels  and 
the  improvement  of  the  contraction  of  the  heart,  with  an  increase 
of  its  "minute  volume,"  occur  at  the  same  time.  From  such  experi- 
ments, it  seems  probable  that  in  the  living  body  also  the  dilatation  of 
the  renal  vessels  and  the  contraction  of  the  intestinal  vessels  occur 
during  the  same  stage  of  the  pharmacological  action  as  do  the  favor- 
able effects,  on  the  cardiac  function. 

Eecent  observations  made  on  normal  men  by  0.  Miiller,  Vagt,  and 
Eychmiiller  do  not  agree  with  this  view.  These  authors  were  not  able 
to  demonstrate  a  constriction  of  the  intestinal  vessels  after  intra- 
venous injection  of  digitalis  bodies,  although  a  distinct  but  slight 
effect  on  the  heart  was  produced.  As  these  doses  also  produced  no 
diuretic  effect,  they  therefore  were  not  large  enough  to  cause  dilatation 
of  the  renal  vessels  in  healthy  subjects.  It  was  not  possible  to  observe 
the  behavior  of  the  intestinal  vessels  in  patients  with  cardiac  disease, 
in  whom  the  same  doses  produced  pronounced  effects  on  the  heart  and 
increased  diuresis.  It  appears  to  the  authors  (G.  and  M.},  however, 
that  the  conditions  obtaining  in  a  pathologically  disordered  circu- 
lation are  too  complicated  to  justify  a  conclusion  that  vasomotor 
changes  do  not  occur  in  internal  organs  simply  because  the  plethysmo- 
jrraphic  curves  obtained  from  the  arm  fail  to  indicate  their  occurrence. 

In  cardiac  disease  the  effects  produced  on  the  heart  function  appear 


THEORY  OF  DIGITALIS  ACTION  299 

to  be  the  most  essential  reason  for  the  usefulness  of  these  drugs,  but 
the  vasoconstricting  action  on  the  vessels  of  the  intestines  and  liver 
also  appears  to  be  beneficial.  The  clinical  picture  observed  in  patients, 
in  whom  stasis  due  to  cardiac  disease  is  present,  indicates,  as  empha- 
sized by  Sahli,  that  not  only  the  great  vessels  but  also  the  whole 
portal  system  is  over-distended  with  blood.  Vasoconstriction  in  this 
system — which,  as  is  well  known,  may  contain  extremely  large  amounts 
of  blood — can  be  of  great  assistance  to  the  heart  by  starting  this 
stagnating  blood  to  flowing  again  so  that  it  may  aid  in  filling  other 
vascular  systems. 

Against  the  view  that  the  vascular  actions,  of  digitalis  play  any 
part  in  causing  the  benefits  obtained  from  its  therapeutic  employment, 
objection  has  been  raised,  on  the  assumption  that  a  Vasoconstriction 
entails  the  burdening  of  the  heart  with  a  great  task,  and  that  therefore 
drugs  of  the  digitalis  group  would  be  poor  agents  to  use  to  aid  a  strug- 
gling heart  if  they  increase  the  resistance  against  which  the  heart  must 
expel  its  contents.  This  objection  would  be  justified  if  these  drugs, 
in  therapeutic  dosage,  caused  a  general  Vasoconstriction.  However, 
small  therapeutic  doses  affect  practically  only  the  vessels  most  sus- 
ceptible to  their  influence,  namely,  those  of  the  portal  system.  As  the 
Wood  is  thus  forced  from  the  vessels  of  the  intestines  and  liver  into 
other  vascular  systems,  which  are  not  constricted  by  these  doses, — 
for  example,  into  the  renal  vessels,  which  are  in  fact  dilated  under  the 
influence  of  digitalis, — the  resistance  of  the  total  cross-section  of  the 
vascular  tree  need  not  be  increased  to  an  extent  greater  than  is  com- 
pensated for  by  the  increased  efficiency  of  the  heart  action. 

Behavior  of  the  Renal  Vessels. — A  second  weighty  objection  rests 
on  the  behavior  of  the  urinary  secretion,  for  the  increased  diuresis 
speaks  against  any  vasoconstricting  action  in  the  kidney,  for  any 
diminution  of  the  blood  flow  through  the  kidney  ordinarily  causes 
diminished  secretion.  However,  Loewi  and  Jonescu-  have  shown  that 
the  renal  vessels,  in  contradistinction  to  the  vessels  of  the  intestines, 
are  not  contracted  but  are  dilated  by  the  small  doses  of  digitalis,  or 
other  members  of  this  group,  which  correspond  to  those  used  in  thera- 
peutics. Very  small  doses  of  strophanthin,  while  causing  a  constric- 
tion of  the  intestinal  vessels,  produce  little  or  no  change  in  the  blood- 
pressure,  but  still  they  stimulate  diuresis.  Moreover,  the  surviving 
renal  vessels  are  dilated  by  the  digitalis  bodies  in  concentrations  which 
constrict  the  intestinal  vessels,  and  are  constricted  only  by  much 
stronger  solutions  (p.  287).  The  renal  vessels  are,  therefore,  one  of 
the  vascular  systems  which  profit  by  the  forcing  out  of  the  blood 
from  the  primarily  constricted  portal  system. 

From  the  above  it  would  appear  that  vasomotor  effects  may  well 
play  a  role  in  the  therapeutic  use  of  digitalis.  As  a  result  of  the  fact 
that,  if  stasis  be  present,  the  vasoconstricting  action  is  more  pro- 
oinced  in  the  vessels  of  the  portal  system,  a  new  redistribution  of 


300  PHARMACOLOGY  OF  CIRCULATION 

the  blood  occurs,  the  blood  being  forced  along  not  only  from  the 
veins  into  the  arteries  of  the  general  circulation  but  also  from  the 
passively  congested  liver  and  intestines  into  other  parts  of  the  body. 

In  still  another  way  the  actions  on  the  vessels  may  be  of  moment.  Recent 
investigations  (Hasebroek,  Griitzner)  make  it  probable  that  the  active  rhythmic 
contraction  of  the  smallest  vessels  contributes  to  the  maintenance  of  the  circu- 
lation. If  this  be  true,  the  action  of  digitalis  on  the  vessels  may  be  of  value  as 
aiding  in  forcing  the  blood  along  in  the  capillaries,  and  the  absorption  of  oedema 
may  thus  be  facilitated. 

A  consideration  of  the  conditions  obtaining  in  pathological  dis- 
turbances of  the  circulation  thus  leads  to  the  following  conception 
of  its  beneficial  therapeutic  action :  Digitalis  enables  a  ventricle,  which 
has  become  insufficient,  again  to  contract  more  completely,  and  brings 
about  a  better  flow  of  blood  through  the  organ.  This  results  in  the 
disappearance  of  the  vasoconstriction  in  the  large  vascular  systems 
which,  in  spite  of  existing  stasis,  has  maintained  the  blood-pressure. 
With  the  restoration  of  an  efficient  functional  activity  of  the  heart,  the 
conditions  of  blood-pressure  and  blood  flow  return  to  the  normal, 
and  the  blood  which  has  collected  in  the  venous  systems  is  brought 
back  again  into  the  arterial  systems.  The  contraction  of  the  vessels 
of  the  intestines  and  liver  forces  out  the  blood  collected  there,  so 
that  the  vessels  in  other  organs — e.g.,  the  kidney,  brain,  and  peripheral 
parts  of  the  body — are  better  filed,  and  the  abnormal  distribution 
of  the  blood  is  replaced  by  a  normal  one. 

[As  first  shown  clinically  by  McKenzie  and  as  emphasized  by  all  the  more 
recent  careful  studies  of  the  effects  of  digitalis  in  patients  with  cardiac  disease, 
the  action  of  digitalis  in  lessening  or  abolishing  the  conductivity  of  the  bundle 
of  His  (pages  266  and  294)  is  the  most  decisively  beneficial  effect  produced  by 
it  in  a  large  group  of  cases.  It  is  this  power  of  protecting  the  ventricle  from  a 
constant  shower  of  stimuli  arising  in  the  fibrillating  auricle,  which  is  chiefly 
responsible  for  the  almost  miraculously  curative  action  of  the  drug  in  many  cases 
of  threatening  failure  of  the  circulation. — TK.] 

BIBLIOGRAPHY 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  158. 

Bohm:  Pfluger's  Arch.,  1872,  vol.  5,  p.  153. 

Eychmliller:   Berl.  klin.  Woch.,  1909,  No.  37. 

Fahrenkamp:  Heidelberg,  unpublished  experiments. 

Frank:  Ztschr.  f.  BioL,  1901,  vol.  41,  p.  1. 

Frankel:  Miinchn.  med.  Woch.,  1905,  No.  32. 

Frankel  u.  Schwartz:  Arch.  f.  exp.  path.  u.  Pharm.,  1907,  vol.  57,  p.  79. 

Gottlieb:  Medizinische  Klinik,  1906,  No.  37,  p.  955. 

Griitzner:  Arch.  f.  Psychiatric,  1906,  vol.  42,  p.  1,  and  Deut.  Arch.  f.  klin.  Med., 

1907,  vol.  89,  p.  131. 

Hasebroek:  Ztschr.  f.  klin.  Med.,  1903,  vol.  77. 
v.  Hofmann:  Pfluger's  Arch.,  1901,  vol.  84,  p.  130. 
Lang  u.  Manswetowa:  Arch.  f.  klin.  Med.,  1908,  vol.  94,  p.  455. 
Loewi  u.  Jonescu:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59,  p.  71. 
Magnus  u.  Sowton:   Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  255. 
Miiller,  Otfried:  Verb.  d.  26.  Kongr.  f.  innere  Med.,  Wiesbaden,  1909. 
Sahli:  Verh.  d.  21.  Kongr.  f.  innere  Med.,  Berlin,  1901. 
Tigerstedt,  K.:   Skand.  Arch.  f.  Physiol.,  1907,  vol.  20,  p.  115. 
Vagt:  Med.  Klinik,  1909. 


CLINICAL  ASPECTS  OF  DIGITALIS  301 

PRACTICAL  EMPLOYMENT  OF  DIGITALIS 

Digitalis  leaves  were  formerly  used  in  England  as  a  household 
remedy  for  dropsy,  but  had  been  forgotten  when  Withering,  in  the 
last  half  of  the  eighteenth  century,  recognized  their  great  value,  and, 
after  using  them  for  a  decade,  published  his  results.  As  has  long 
been  known  by  clinicians,  though  only  comparatively  recently  defi- 
nitely demonstrated  by  physiological  assay,  the  pharmacological  activ- 
ity of  the  leaves  is  very  variable,  and  differs  with*  the  locality  from 
which  they  have  been  obtained,  the  age  of  the  plants,  and  the  time 
elapsed  since  they  have  been  gathered,  as  well  as  with  the  conditions 
under  which  they  have  been  prepared  and  preserved.  This  variation 
in  the  activity  of  different  digitalis  preparations,  the  importance  of 
which  has  only  recently  been  recognized,  is  perhaps  the  chief  reason 
why  this  drug,  even  after  extensive  use  for  125  years,  is  not  yet  gener- 
ally administered  according  to  generally  recognized  and  fully  estab- 
lished rules,  but  is  ordinarily  employed  by  the  individual  physician 
according  to  his  own  subjective  experience  and  impressions.  Prepara- 
tions assayed  by  physiological  tests  are  now  obtainable  and  widely  used. 
ACTIVE  PRINCIPLES. — Among  the  definitely  constituted  active  prin- 
ciples of  the  digitalis  leaves  are  the  almost  insoluble  crystalline 
digitoxin,  first  prepared  by  Schmiedeberg  (the  digitaline  nativelle 
of  the  French),  and  the  rather  insoluble  digitalin  of  Schmiedeberg 
and  Kiliani.  In  addition,  digitalis  leaves  contain  water-soluble  gluco- 
sides  named,  by  Schmiedeberg,  digitaleins.  All  these  substances  possess 
typical  digitalis  actions,  digitoxin  being  the  most  active  and  powerful. 
In  the  leaves  they  probably  occur  chiefly  in  the  form  of  combinations 
with  the  tannic  acid,  which  in  pure  form  are  insoluble  in  water  but  are 
readily  soluble  in  dilute  alkalies. 

In  addition  to  these  useful  pure  principles,  there  are  also  present  a  number 
of  digitonins,  which  are  saponins  and  do  not  possess  the  physiological  actions  of 
the  digitalis  bodies.  On  account  of  their  local  irritating  actions,  they  often 
play  a  part  in  the  causation  of  digestive  disturbances  which  not  infrequently 
develop  in  the  therapeutic  use  of  digitalis.  [They  also  probably  aid  in  bringing 
the  insoluble  and  useful  active  principle  into  solution,  as,  for  example,  in  the 
infusion. — TB.] 

Digalen  is  a  proprietary  preparation  of  the  active  principles  dissolved  in 
water  and  glycerin.  According  to  Cloetta,  it  contains  a  soluble  digitoxin,  but 
according  to  Kiliani  only  an  impure  digitalein.  [Hatcher  has  shown  that  the 
claims  made  for  the  activity  of  this  preparation  are  greatly  exaggerated,  its 
strength  being  only  that  of  a  standard  tincture.  In  laboratory  tests  made  by 
the  translator,  this  preparation  has  been  found  to  be  of  inconstant  strength, 
probably  on  account  of  deterioration  on  keeping  for  any  length  of  time. — TB.] 

METHODS  OF  ASSAY. — The  digitoxin  contents  of  digitalis  leaves 
may  be  determined  chemically,  but  it  does  not  run  parallel  with  the 
physiological  activity  of  the  leaves,  for  the  leaves  are  much  more 
active  than  can  be  accounted  for  by  the  digitoxin  present  (Ziegenbein, 
Focke).  As  the  other  active  principles  cannot  be  estimated  by 
chemical  methods,  physiological  methods  are  the  only  ones  available 


302  PHARMACOLOGY  OF  CIRCULATION 

for  the  determination  of  the  activity  of  the  leaves  or  the  galenic  prep- 
arations made  from  them. 

Necessity  of  Assay. — The  determination  of  physiological  activity  of  these 
drugs  is  necessary  because  it  varies  so  greatly  in  different  specimens  and  in  the 
different  preparations  made  from  them.  Ziegenbein  found  differences  of  100-200 
per  cent,  in  the  activity  of  the  leaves  gathered  the  same  year  but  coming  from 
different  localities.  Of  still  greater  significance  is  the  deterioration  which  takes 
place  in  the  course  of  a  year  in  leaves  preserved  according  to  the  directions  given 
by  the  pharmacopoeia  (Focke).  At  times  this  amounts  to  a  loss  of  25  per  cent, 
of  their  activity.  It  is  thus  easy  to  understand  the  great  variations  in  the 
activity  of  different  galenic  preparations  which  with  the  tincture  may  amount  to 
as  much  as  400  per  cent.  (Frankel1) .  There  consequently  is  no  other  drug  where 
it  is  more  important  to  substitute  for  preparations  of  uncertain  therapeutic 
activity  those  of  known  efficiency  or  pure  substances  of  constant  composition. 
Only  thus  can  the  therapeutic  use  of  the  drug  become  more  accurate.  [Not  only 
the  leaves  but  also  the  galenic  preparations  deteriorate  on  keeping.  As  is  widely 
known,  this  is  especially  true  of  the  infusion,  which  deteriorates  with  such  rapid- 
ity that  it  should  be  used  only  when  freshly  prepared.  The  fluidextracts  appear 
to  deteriorate  but  slowly.  The  translator  found  a  deterioration  of  but  30  per  cent, 
in  a  fluidextract  which  had  been  kept  for  three  years  in  his  laboratory. — TB.] 

The  physiological  assay  of  digitalis  and  its  preparations  may  be 
made  with  sufficient  accuracy  for  practical  purposes  by  determining 
the  minimal  dose  which  stops  the  heart  in  systole  35-40  minutes  after 
injection  into  the  lymph-sac  of  the  frog  (R.  temporaria) . 

Employment  of  their  pure  active  principles  would  be  another  way 
to  secure  exact  dosage  for  the  drugs  of  this  group,  which,  besides  the 
active  principles  present  in  the  digitalis  leaves,  includes  a  number  of 
substances,  chiefly  glucosides,  derived  from  different  sources.  From 
a  practical  point  of  view  the  different  strophanthins  are  the  most 
important  of  these. 

Of  these  there  are  at  least  two  known  and  well  characterized, — one  known 
as  Strophanthin  Bohringer,  or  Strophanthin  Merck,  which  is  amorphous  and  is 
derived  from  Strophanthus  kombe  or  Str.  hispidus.  The  other,  G- Strophanthin  * 
(Str.  Thorns),  is  crystallizable  and  is  obtained  from  Str.  gratus.  These  strophan- 
thins are  readily  soluble  in  water,  as  are  convallamarin  (from  Convallaria 
majalis),  helleborein  (from  the  different  species  of  Hellebore),  adonidin  (from 
Adonis  vernalis),  and  the  alkaloid  erythrophlein.  Strophanthin  has  proved  espe- 
cially suitable  for  intravenous  administration.  The  other  substances  named  have 
thus  far  acquired  no  particular  practical  importance. 

A  number  of  other  glucosides  of  the  digitalis  group  are  present  in  various 
arrow-poisons,  but  they  possess  chiefly  a  toxicological  interest.  Such  are,  for 
example,  echuyin  (from  a  West  African  arrow-poison,  antiarin  (from  Antiaris 
toxicaria),  and  euonymotoxin  (from  Euonymus  atropurpureus).  A  non-crystal- 
lizable  glucoside  with  digitalis  actions,  scillain,  is  the  active  principle  of  squills 
(from  Scilla  maritima),  a  drug  formerly  much  employed. 

DIFFERENCES  IN  THE  ACTIONS  OF  DIFFERENT  DIGITALIS  BODIES. — 
The  pharmacological  actions  of  these  different  pure  principles  are 
by  no  means  identical,  for,  although  they  all  act  on  the  same  elements 
in  the  various  organs, — i.e.,  have  the  same  seats  of  action,  and  exert 
a  qualitatively  similar  pharmacological  action, — more  refined  pharma- 
cological analysis  has  shown  many  rather  important  quantitative 

*  [Ouabain  is  synonymous  with  G.  Strophanthin. — TB.] 


CLINICAL  ASPECTS  OF  DIGITALIS  SOS 

differences,  not  only  in  their  actions  on  the  cardiac  muscle  and 
ganglia,  but  also  in  their  vasomotor  actions,  these  being  more  pro- 
nounced,— for  example,  with  digitoxin  than  with  the  others  (Gottlieb 
u.  Magnus).  The  power  of  slowing  the  heart  is  another  action  which, 
is  possessed  in  varying  degrees  by  various  members  of  this  group 
(Kochmann) . 

Of  greater  practical  importance  are  the  differences  manifested  as. 
regards  the  local  irritant  action  in  the  stomach,  and,  above  all,  in 
connection  with  their  absorbability  and  their  excretion.  In  this  last- 
mentioned  connection  the  soluble  strophanthins  and  the  insoluble 
digitoxin  are  especially  contrasted.  In  general,  those  substances 
which  are  soluble  in  water  act  more  promptly  than  those  which  are 
insoluble  in  water. 

Cumulative  Properties. — The  different  members  of  this  group  also 
differ  from  one  another  in  respect  to  their  so-called  cumulative  actions, 
although  all  of  them  exhibit  the  peculiar  pharmacological  behavior 
that,  once  their  effects  have  been  obtained,  the  effects  persist  for  a 
considerable  time.  Obviously  these  substances  are  stored  up  in  the 
heart.  The  degree  and  duration  of  their  action  depend  on  the  amount 
thus  stored  up,  the  relatively  long-continued  action  of  single  doses 
being  explained  by  the  fact  that,  once  this  combination  of  the  drug 
with  some  as  yet  undetermined  elements  in  the  heart  has  taken  place, 
it  is  but  slowly  broken  up  again.  By  continued  administration  of 
new  doses  the  heart  continues  to  absorb  larger  and  larger  amounts,, 
and,  as  a  result  of  the  continued  absorption,  in  the  course  of  several 
days  the  physiological  action  may  bo  developed  to  the  desired  degree. 

With  all  the  drugs  of  this  group,  still  further  administration, 
may  lead  to  a  so-called  cumulation,  due  to  an  accumulation  of  the 
drug  in  the  heart  in  amounts  larger  than  is  desired.  The  persistence 
of  the  action  is  quite  independent  of  the  rapidity  with  which  it 
develops,  for  a  fairly  lasting  effect  may  be  obtained  immediately 
after  the  intravenous  injection  of  an  efficient  dose  of  strophanthin, 
or  much  later  by  the  oral  administration  of  digitalis  leaves,  which 
ordinarily  produce  the  typical  effects  on  the  circulation  only  after 
24  hours,  or  even  much  later.  However,  the  different  digitalis  bodies 
show  marked  differences  in  the  degree  and  intensity  of  this  lasting 
action,  and  these  are  of  decisive  importance  for  the  occurrence  of 
cumulation,  as  this  depends  on  the  summation  of  the  actions  of  new 
doses  with  the  persisting  actions  of  the  earlier  ones. 

The  symptoms  of  cumulation  are  similar  to  those  resulting  from 
the  administration  of  single  toxic  doses.  The  first  are  usually  nausea* 
vomiting,  and  diarrho3a,  succeeded  in  more  pronounced  cases  by 
alarming  retardation  and  arrhythmia  of  the  pulse.  The  sudden  change 
from  a  slow  to  a  rapid  pulse  seen  in  animals  poisoned  by  digitalis 
may  occur,  but  not  necessarily  so  even  in  most  severe  poisoning  in 


304  PHARMACOLOGY  OF  CIRCULATION 

The  vomiting,  which  occurs  in  cumulation,  is  a  symptom  produced 
by  the  drug  after  absorption,  and  is  not  to  be  confounded  with  that 
due  to  local  irritation  of  the  stomach,  which  often  occurs  in  susceptible 
individuals  after  the  first  doses  of  digitalis  bodies.  This  local  irritation 
in  the  alimentary  canal  is  caused  not  only  by  the  useful  active  princi- 
ples but  also  by  the  digitonins,  the  saponin-like  constituents  of  the 
digitalis  leaves. 

Differences  in  Liability  to  Cause  Cumulation. — Comparative  in- 
vestigations in  animals  have  shown  that  the  circulatory  effect  develops 
a  few  hours  after  the  subcutaneous  injection  of  strophanthin,  while 
after  injection  of  digitalis  or  digitoxin  a  much  longer  period  elapses. 
On  the  other  hand,  the  effects  of  strophanthin  last  a  much  shorter 
time  than  those  of  digitalis  or  digitoxin.  The  effects  of  this  last- 
named  glucoside  are  especially  persistent,  so  that  the  interval  between 
doses  must  be  longer  when  it  is  used,  if  cumulative  effects  are  to  be 
avoided  (Frdnkel2).  Digalen  (see  p.  301)  also  has  a  well-developed 
cumulative  action  (Frdnkel3).  This  property  of  causing  cumulative 
effect  is,  however,  necessarily  present  in  any  drug  possessing  the  typi- 
cal digitalis  actions  and  is  essential  for  securing  the  desirable  lasting 
therapeutic  effects.  Therefore,  cumulative  action  may  always  result 
from  continued  administration  of  any  member  of  this  group. 

PRINCIPLES  GOVERNING  THE  DOSAGE  AND  CHOICE  OF  PREPARATION. — 
In  the  clinical  employment  of  digitalis,  the  attempt  should  be  made  to 
administer  doses  only  large  enough  to  secure  the  necessary  lasting 
effects  without  causing  the  symptoms  of  cumulation  to  appear.  The 
use  of  physiologically  assayed  preparations  is  the  best  means  of  accom- 
plishing this.  [Very  frequently,  however,  as  emphasized  by  Mc- 
Kenzie,  the  desired  effect  on  the  heart  may  be  obtained  only  by 
dbses  which  also  cause  nausea  and  vomiting.  The  danger  from  the 
cumulative  action  of  digitalis  has  been  generally  over-emphasized  by 
pharmacologists  and  by  many  clinicians. — TR.] 

The  employment  of  the  pure  active  principles  has  thus  far  not  been 
widely  favored  in  Germany,  but  in  France  digitoxin  is  much  employed, 
in  spite  of  its  pronounced  tendency  to  cause  cumulative  effects  (Marx, 
Zeltner] .  Digitalin  would  appear  to  possess  insufficient  physiological 
activity  for  practical  therapeutic  administration.  [Probably  because 
usually  used  in  too  small  doses. — TR.]  Besides  this,  it  is  decomposed 
in  the  stomach  to  a  considerable  and  indeterminable  extent  (Deucher). 
Although  the  strophanthins  are  so  efficient  when  administered  intra- 
venously, they  are  but  moderately  active  and  the  effects  produced  by 
them  are  not  lasting  when  they  are  administered  by  mouth.  [This  is 
perhaps  in  part  due  to  the  fact  that  they  are  excreted  by  the  kidney 
more  rapidly  than  they  are  absorbed  from  the  alimentary  canal. — TR.] 

The  curative  effects  obtained  by  the  use  of  digitalis  are  the  result 
of  the  combined  actions  of  the  various  substances  contained  in  the 
leaves.  As  these  substances  exhibit  marked  differences  from  one 


CLINICAL  ASPECTS  OF  DIGITALIS  305 

another  in  the  character  of  their  actions,  in  their  rates  of  absorption, 
and  in  the  persistence  of  their  actions,  it  is  very  possible  that  the 
advantages  claimed  for  the  leaves  or  their  preparations  are  due  to 
their  containing  this  combination  of  substances.  Until  these  conditions 
are  more  thoroughly  comprehended  from  a  pharmacological  point  of 
view,  it  is,  as  a  rule,  therapeutically  correct  to  give  preference  to  the 
oral  administration  of  the  leaves  or  their  galenic  preparations. 

The  DOSAGE  OF  DIGITALIS  leaves  and  of  their  galenic  preparations 
varies  with  the  length  of  time  that  the  drug  is  to  be  administered.  The 
total  amount  administered  during  the  whole  treatment  is  much 
more  important  than  the  size  of  the  individual  doses.  This  is  so 
because  of  the  slow  absorption  of  the  active  principles  and  their 
accumulation  in  the  heart,  as  well  as  because  of  their  characteristic 
power  to  produce  somewhat  lasting  effects.  (Maximal  dose  0.2  gm., 
1.0  gm.  per  diem.)  As  a  general  rule,  three  or  four  doses  of  0.1  gm. 
each  of  a  good  active  digitalis  powder  per  diem  may  be  given,  and  such 
administration  may  be  persisted  in  for  three  or  four  days,  but  in 
such  dosage  not  for  a  longer  period.  [Much  larger  doses,  such  as 
4.0-8.0  c.c.  of  the  tincture,  may  be  given  every  24  hours  for  several 
days  without  danger,  if  the  patient  is  kept  quiet  and  under  careful 
observation.  In  fact,  at  times  it  is  only  by  the  use  of  such  doses, 
or  even  larger  ones,  that  the  desired  beneficial  actions  may  be 
obtained. — TR.] 

If  the  full  therapeutic  effect  is  obtained  on  the  second  or  third 
day,  most  competent  authorities  advise  its  discontinuation  for  a  time 
or  a  diminution  of  the  daily  dose.  In  this  way  the  cumulative  action 
is  most  surely  avoided.  Other  observers  believe  that  the  good  effects 
of  a  digitalis  cure  are  more  lasting  if  the  administration  be  con- 
tinued, even  after  the  appearance  of  the  desired  actions,  until  from  2.0 
to  2.5  gm.  in  all  have  been  taken.  Others  advise  the  continued 
administration  of  smaller  doses,  about  0.1  gm.  per  diem,  which  can  be 
Jen  for  a  long  time  without  the  development  of  cumulation.  [As  a 
itter  of  fact,  the  dose  for  each  case  must  be  determined  by  trial. — 

.] 

The  infusion  of  digitalis  is  preferred  by  many  physicians,  but  is 
very  unstable  (Loewi}  and  is  weaker  and  more  uncertain  in  its  action, 
because,  according  to  the  care  with  which  it  is  prepared,  varying  por- 
tions of  the  active  principles  may  be  extracted  from  the  leaves.  On 
the  other  hand,  it  is  claimed  that  the  infusion  is  less  likely  directly 
to  irritate  the  stomach,  perhaps  because  it  contains  only  a  smaller 
amount  of  the  active  principles,  but  also  perhaps  because  fewer  of  the 
contaminating  substances  are  extracted  from  the  leaves.  Similar 
advantages  may  be  possessed  by  other  extracts, — for  example,  the 
quite  stable  dialysate, — as  well  as  by  the  tincture,  which  is  so  often 
preferred  for  long-continued  use. 
20 


306  PHARMACOLOGY  OF  CIRCULATION 

Digipuratum. — During  the  preparation  of  digipuratum,  an  extract 
of  purified  digitalis,  the  elimination  of  inactive  contaminating  sub- 
stances is  carried  still  further,  for  as  much  as  90  per  cent,  of  the 
solid  constituents  may  be  removed  from  alcoholic  extracts  of  the 
leaves  without  diminishing  their  physiological  or  therapeutic  activity. 
It  would  appear  that  this  preparation  is  especially  free  from  digitonin 
and  other  saponin-like  components  of  the  crude  drug,  for  it  represents 
in  almost  pure  form  the  combinations  of  tannic  acid  and  the  active 
glucosides.  These  are  insoluble  in  the  stomach,  and  therefore  irritate 
its  mucous  membrane  but  slightly,  while,  in  the  alkaline  intestinal 
contents,  they  are  readily  soluble,  and  therefore  relatively  easily 
absorbed.  According  to  some  observers  (Hopffner},  this  preparation 
disturbs  the  stomach  less  than  all  other  digitalis  preparations  of  equal 
physiological  activity.* 

INTRAVENOUS  ADMINISTRATION. — When  in  critical  cases  it  is  im- 
portant to  obtain  the  effect  of  digitalis  more  rapidly  than  is  possible 
by  oral  administration,  intravenous  administration  may,  with  great 
advantage,  be  employed.  The  subcutaneous  or  intramuscular  injection 
of  all  active  digitalis  preparations  is  painful,  and,  if  really  effective 
doses  are  thus  administered,  marked  local  irritation  results,  while  the 
subcutaneous  injections  of  weaker  preparations  or  of  relatively  high 
dilutions  possess  no  advantage  over  their  administration  by  mouth 
[except  that  at  times  the  stomach  rejects  all  medication  administered 
orally.  In  such  cases  the  rectal  administration  of  relatively  large 
doses  in  moderate  dilution  may  be  followed  by  gratifying  results. — 
TR.]. 

After  intravenous  injection  of  suitable  preparations  of  digitalis, 
the  effects  on  the  circulation  may  manifest  themselves  within  a  few 
minutes,  and  the  favorable  action  is  usually  fully  developed  at  the 
end  of  an  hour  and  often  lasts  for  a  long  time  [12  to  24  hours  or 
more. — TR.].  Only  pure  substances  readily  soluble  in  water  should 
be  used  for  this  purpose.  This  method  was  first  employed  by  Kott- 
mann,  who  used  digalen  for  this  purpose,  but,  since  its  recommen- 
dation by  Frdnkel  and  Schwartz,  strophanthin  in  dosage  of  0.5-1.0 

*  [Inasmuch  as  both  clinical  experience  and  such  laboratory  investigations 
as  those  of  Hatcher  have  clearly  demonstrated  that  the  nausea  and  vomiting 
produced  by  digitalis  is  usually  the  result  of  its  action  on  the  vomiting  centres, 
and  as  the  desired  effects  on  the  circulation  often  manifest  themselves  only  with 
doses  which  also  produce  these  undesirable  effects,  one  must  accept  with  extreme 
caution  the  claims  made  for  any  preparation  of  digitalis  or  any  of  its  group 
that  it  does  not  cause  gastric  disturbances.  Ordinarily  this  is  equivalent  to 
stating  that  the  preparation  is  more  or  less  inert  in  other  particulars.  The 
claimed  superiority  of  digipuratum  in  this  respect  may  appear  to  be  justified 
by  clinical  observation,  but  the  translator  has  seen  it  cause  typical  digitalis 
vomiting.  If  this  drug  is  really  less  likely  to  upset  the  stomach  when  given  in 
therapeutic  doses,  it  is  perhaps  due  to  the  convenience  with  which  sufficient 
amounts  may  be  given  without  causing  the  patient  to  swallow  nauseous  tasting 
mixtures  or  draughts. — TE.] 


TREATMENT  OF  CIRCULATORY  FAILURE  307 

ing.  has  proved  an  important  advance  in  therapeutics.*  [Cushny  and 
Dock  over  ten  years  ago  injected  a  dilute  solution  of  digitalis  into 
the  vein  of  a  human  patient,  with  temporary  good  results. — Personal 
communication  to  translator.] 

BIBLIOGRAPHY 

Boos:  Archiv  of  Internal  Medicine,  1911,  No.  4. 

Cloetta:   Munchn.  med.  Woch.,  1904,  No.  33,  p.  1466. 

Deucher:  Arch.  f.  klin.  Med.,  1896,  vol.  62. 

Focke:   Arch.  f.  Pharm.,  1903,  vol.  241,  p.  669. 

Focke:   Therap.  d.  Gegenwart,  June,   1904. 

^Frankel:    Therap.  d.  Gegenwart,  March,  1902. 

"Frankel:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  51,  p.  84;  1907,  vol.  57,  p.  123. 

"Friinkel:   Ergebnisse  d.  inn.  Med.,   1908,  vol.  1,  p.  68. 

Friinkel  u.  Schwartz:   Arch.  f.  Path.  u.  Pharm.,  1906,  vol.  57. 

Gottlieb  u.  Tambach:   Munchn.  med.  Woch.,  1911,  No.  1. 

Gottlieb  u.  Magnus:    Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  47,  p.  135. 

Hopffner:  Munchn.  med.  Woch.,  1908,  No.  34. 

Kiliani:   Munchn.  med.  Woch.,  1907,  No.  18. 

Kochmann:  Arch,  intern,  de  Pharmacodyn.  et  de  Therap.,  1906,  vol.  16,  p.  221. 

Kottmann:   Ztschr.  f.  klin.  Med.,  1905,  vol.  56. 

Loewi :   Wien.  klin.  Woch.,  1906,  No.  39. 

Marx:   Inaug.  Diss.,  Strassburg,  1898. 

Miiller,  Leo:   Miinchn.  med.  Woch.,  1908,  No.  51. 

Schmiedeberg :   Arch.  f.  exp.  Path.  u.  Pharm.,  1874,  vol.  3,  p.  16. 

Zeltner:   Munchn.  med.  Woch.,  1900,  No.  26. 

Ziegenbein:  Arch.  f.  Pharm.,  1902,  vol.  240,  No.  6,  p.  454. 

TREATMENT  OF  CARDIAC  AND  VASCULAR  DEPRESSION 

By  cardiac  weakness  is  understood  a  disturbance  of  the  circulation 
which  is  characterized  by  weak,  rapid,  and  often  irregular  pulse, 
pallor,  and  sometimes  cyanosis.  Such  conditions  may  develop  in  the 
final  stages  of  many  kinds  of  poisoning  as  well  as  in  the  course  of 
various  infectious  diseases.  In  an  earlier  section  (p.  290)  it  has  been 
stated  that  cardiac  insufficiency,  which  is  equally  pronounced  in  both 
right  and  left  hearts,  results  only  in  a  slowing  up  of  the  blood  flow 
without  the  occurrence  of  stasis.  This  would  typify  the  conditions 
in  a  case  of  uncomplicated  depression,  but,  as  a  matter  of  fact, 
except  as  a  result  of  hemorrhage,  cardiac  weakness  is  never  observed 
except  in  combination  with  a  more  or  less  general  vasoparesis,  for  not 
only  the  toxins  of  infectious  diseases,  but  also  other  cardiac  depres- 
sants, such  as  chloral  hydrate,  chloroform,  arsenic,  etc.,  affect  both 
e  heart  and  the  vasomotor  centres  [or  the  vessels  themselves. — TR.]. 


[It  should  be  emphasized  that  strophanthin  and  ouabein  are  both  enormously 
ic  substances.  Since  their  introduction  as  drugs  to  be  administered  intra- 
nously,  clinicians  have  learned  that  their  administration  is  not  unattended 
with  danger.  0.3  mg.  is  ordinarily  a  sufficient  initial  dose  and,  in  the  translator's 
opinion,  0.5  mg.  is  the  largest  amount  that  should  be  given  as  a  first  dose. 
Further,  all  those  who  have  used  these  drugs  at  all  extensively  insist  on  the 
extreme  danger  of  giving  them  to  patients  who  have  recently  taken  any  con- 
siderable amounts  of  digitalis  or  its  congeners.  Two  days  or  so  should  be 
allowed  to  elapse  between  the  last  considerable  digitalis  dosage  given  by  mouth 
and  the  intravenous  administration  of  strophanthin  or  ouabein. — TR.] 


308  PHARMACOLOGY  OF  CIRCULATION 

Consequently,  the  phenomena  resulting  from  vasomotor  depression 
develop  simultaneously  with  those  resulting  from  cardiac  insufficiency, 
or  precede  or  follow  them.  Moreover,  even  if  the  heart  is  not  directly 
affected  by  the  toxic  agents,  vasomotor  depression  being  the  primary 
condition,  cardiac  weakness  develops  secondarily,  for,  as  stated  in  the 
introductory  portion  of  this  chapter,  the  functions  of  the  heart 
and  of  the  vessels  reciprocally  affect  each  other  most  markedly. 

A  vasoparesis  in  the  splanchnic  system  produces  the  most  severe 
disturbances  of  the  circulation.  Under  normal  conditions  the  vessels 
of  the  abdominal  viscera  are  maintained  in  a  state  of  moderate  con- 
traction by  the  constantly  acting  influence  of  the  vasomotor  centres. 
If  this  influence  be  removed,  the  vessels  dilate  and  become  a  reservoir 
of  such  great  capacity  that  its  filling  deprives  the  other  vascular  sys- 
tems of  most  of  their  blood.  At  the  start  the  organism  compensates 
for  this  by  the  constriction  of  the  vessels  in  other  systems,  and 
pallor,  due  to  contraction  of  the  vessels  of  the  skin  and  muscles, 
appears  before  the  general  blood-pressure  has  sunk  appreciably.  From 
the  teleological  point  of  view,  this  regulating  process  appears  useful, 
as  thus  the  blood  flow  through  the  heart  and  nervous  system  is  main- 
tained as  long  as  possible,  for  when  this  fails  the  general  blood- 
pressure  must  sink  so  decidedly  that  the  insufficient  blood  flow  in 
the  nervous  system  causes  faintness,  while  inadequate  circulation 
through  the  cardiac  muscle  impairs  its  functional  power. 

In  man  the  symptoms  of  such  collapse,  due  chiefly  to  vasoparesis, 
closely  resemble  those  resulting  from  cardiac  weakness.  In  both 
conditions  the  blood-pressure  in  the  aorta  falls,  the  pulse  tension  is 
lowered,  and  the  pulse  becomes  rapid  and  small.  This  acceleration 
is  due  to  the  depression  of  the  vagus  tone,  which,  in  turn,  is  a  conse- 
quence of  the  lowered  blood-pressure.  In  cardiac  failure  the  pulse 
becomes  feeble  and  small  because  the  strength  of  the  cardiac  contrac- 
tions is  primarily  depressed;  in  vasoparesis  the  same  changes  occur 
because  the  heart  contracts  when  insufficiently  filled  with  blood.  In 
primary  cardiac  depression  the  heart  pumps  insufficiently  because  of 
impairment  of  its  power  to  contract,  but  in  vascular  paresis,  even 
though  the  cardiac  muscle  is  capable  of  vigorous  contractions,  so  little 
blood  is  received  by  the  heart  that  only  insufficient  amounts  may  be 
pumped  out  into  the  aorta.  In  each  case  the  effect  on  the  flow  of 
blood  throughout  the  body  is  the  same.  It  is  therefore  clear  that 
cardiac  weakness  and  vascular  depression  may  not  readily  be  differ- 
entiated by  their  symptoms  and  that  they  usually  exist  coincidently. 

Theoretically  they  differ  from  each  other  in  that  in  conditions  of  vaso- 
paresis the  great  veins  of  the  systemic  circulation  are  insufficiently  filled,  while 
in  primary  cardiac  failure  the  blood  accumulates  largely  in  the  veins  of  both  the 
systemic  and  pulmonary  circulations.  It  has,  however,  been  stated  previously 
that  cardiac  weakness  accompanied  by  a  slowing  up  of  the  blood  flow  causes 
merely  an  alteration  in  the  blood  distribution  throughout  the  body  and  is  very 
different  from  those  forms  of  cardiac  insufficiency  for  which  stasis  is  character- 
istic. If  in  cases  with  disturbance  of  cardiac  function  stasis  is  not  markedly 


309 

developed,  there  results  merely  a  diminished  flow  of  blood  throughout  the  whole 
circulation,  a  relatively  insufficient  filling  of  the  arteries,  and  a  fall  in  aortic 
blood-pressure,  just  as  is  the  case  in  conditions  of  vascular  depression. 

Circulatory  failure  resulting  from  vasoparesis  occurs  in  the  ad- 
vanced stages  of  many  toxic  conditions,  the  vasomotor  centres  being 
often  markedly  depressed  by  a  number  of  narcotic  poisons  while  the 
heart  is  still  beating  well  and  the  respiratory  centre  remains  suffi- 
ciently excitable  to  maintain  life.  Although  formerly  in  such  cases 
of  circulatory  failure  it  was  the  custom  to  consider  them  as  due  to 
cardiac  weakness,  Romberg  and  his  coworkers  have  correctly  insisted 
that,  in  the  course  of  infectious  diseases,  disturbances  of  the  circu- 
lation develop  which  closely  resemble  the  picture  seen  in  vasomotor 
paresis.  Using  pneumococci  and  diphtheria  bacilli,  as  well  as  pyocya- 
neus  cultures,  they  were  able  to  show  experimentally  that,  at  any  rate 
during  a  long  period  during  which  the  blood-pressure  continued  to  fall, 
this  was  chiefly  due  to  a  vasoparesis  and  not  to  any  direct  harmful 
action  on  the  heart  (Romberg,  Passler,  Bruhns  u.  Mutter,  Passler  u. 
Roily],  and  that  the  same  holds  true  for  experimentally  induced 
septic  peritonitis  (Romberg  u.  Heinecke). 

In  man  also  the  collapse  occurring  in  such  conditions  may  in 
most  cases  be  attributed  chiefly  to  the  central  vasodepressant  action 
of  the  bacterial  toxins.  However,  Krehl  claims  that  usually,  when  the 
disease  is  at  its  height,  the  heart,  too,  has  been  harmfully  affected,  and 
that  this  is  not  simply  a  secondary  effect  of  the  vasoparesis  but  a 
direct  effect  resulting  from  the  action  of  the  toxins  on  the  heart  itself. 
It  has  been  proved,  especially  for  experimental  diphtheria  intoxication, 
that  in  the  more  advanced  stages  a  progressive  true  cardiac  depression 
is  superimposed  on  the  depression  of  the  vasoconstrictor  centres 
(Roily,  Steyskal).  Other  poisons  causing  depression  of  the  nerve- 
centres  produce  the  same  effects,  lessened  reflexes,  depression  of  the 
vasomotor  and  respiratory  centres,  all  occurring  together  in  such 
poisoning  as  that  induced  by  chloral  hydrate.  In  healthy  animals 
the  heart  is  less  affected  by  this  drug  than  are  the  vital  centres  in 
the  medulla.  The  diseased  heart,  however,  is  much  less  resistant,  so 
that  in  chloral  poisoning,  if  the  heart  be  already  diseased,  death  may 
result  from  cessation  of  the  heart's  action  before  the  respiration 
fails  completely.  It  would  appear  that  diphtheria  toxin  may  act 
lilarly  (Gottlieb}. 

It  was,  therefore,  of  the  highest  clinical  importance  to  obtain,  by 
investigation  of  cases  of  circulatory  failure,  new  criteria  for 
letermining  in  the  individual  case  whether  the  damage  done  to  the 
heart  by  the  toxins  of  the  infection  or  the  vascular  depression  caused 
by  them  is  of  greater  moment,  for  the  choice  of  the  means  used  for 
treating  the  condition  must  be  made  according  to  the  conclusion 
reached.  "With  these  conditions  and  facts  in  mind,  Passler,  using 
ifected  animals,  investigated  the  effect  of  various  cardiac  and  vascu- 


mfectei 


310  PHARMACOLOGY  OF  CIRCULATION 

lar  drugs  in  the  final  stages  of  the  toxaemia,  and  Schwartz  did  the 
same  for  the  earlier  stages.  It  is  clear,  however,  that  the  interpretation 
of  their  experiments  is  attended  by  great  difficulties,  for,  in  the  first 
place,  the  pathological  conditions  on  which  the  drugs  acted  were  not 
sufficiently  understood,  and,  secondly,  most  drugs  affecting  the  func- 
tion of  the  heart  also  act  on  the  vessels  and  vice  versa. 

IN  CASES  IN  WHICH  CARDIAC  INSUFFICIENCY  IS  THE  PREDOMINANT 
FEATURE, 

Digitalis  is  the  first  drug  to  be  thought  of,  but  the  slow  absorption 
of  digitalis  makes  it  self-evident  that  in  acute  circulatory  failure  not 
much  can  be  expected  from  its  oral  administration.  The  intravenous 
injection  of  strophanthin  is,  however,  a  feasible  procedure  from  which 
good  results  might  be  expected,  as  the  injections  are  so  promptly  fol- 
lowed by  the  full  development  of  its  actions,  and,  as  a  matter  of  fact, 
it  has  been  found  clinically  that  an  increase  of  the  volume  of  the  pulse 
and  a  rise  in  blood-pressure  often  follow  the  intravenous  injection  of 
0.5  mg.  of  strophanthin  in  the  collapse  of  typhoid  and  that  of  other 
conditions.  [Crile's  experiments  with  the  intravenous  injection  of 
digitalis  in  animals  suffering  from  shock  would  indicate  that  in 
collapse  of  this  type  strophanthin  would  be  of  no  value,  or  would 
act  harmfully. — TR.] 

Camphor  may  also  improve  the  action  of  the  failing  heart.  It  is 
used  for  this  indication  in  doses  of  0.1-0.5  gm.  dissolved  in  oil,  or  in 
oil  and  ether,  or  in  ether  and  alcohol;  but,  on  account  of  its  insolu- 
bility, it  is  but  slowly  and  uncertainly  absorbed  from  the  stomach. 
By  reason  of  its  volatility  and  its  solubility  in  the  lipoids  of  the 
tissues,  amounts  sufficient  to  produce  effects  on  the  circulation  are 
quite  readily  absorbed  from  the  subcutaneous  tissues  [see  p.  316 — TR.]  , 
"but  its  action  is  rather  evanescent,  for  in  the  body  it  is  transformed 
into  camphor-glycuronic  acid  (Schmeide'berg) . 

Other  Actions. — In  connection  with  the  general  systemic  action  of  camphor 
the  stimulant  action  on  the  cerebral  function  should  again  be  mentioned 
(p.  24).  In  animals  large  doses  cause  clonic  convulsions,  but  these  have  been 
very  rarely  observed  in  man,  as  the  margin  between  therapeutic  and  toxic  doses 
is  so  great.  The  respiratory  and  vasomotor  centres  are  stimulated,  and  increased 
blood  flow  in  the  skin  causes,  even  after  small  doses,  a  subjective  feeling  of 
warmth.  Very  large  doses  produce  an  antipyretic  effect  in  fever.  [Its  local  car- 
minative action  on  the  stomach,  with  the  usual  reflex  effect,  should  also  be 
mentioned.  Moderate  antiseptic  powers  are  also  possessed  by  this  drug. — TB.] 

BIBLIOGRAPHY 

Gottlieb:    Med.  Klin.,  1905,  No.  25. 

Hopffner:  Deut.  Arch.  f.  klin.  Med.,  1908,  vol.  92,  p.  485. 

Krehl:  Pathol.  Physiol.,  Leipzig,  1907,  5th  edition,  p.  119. 

Liebermeister:  Medizin.  Klinik,  1908,  No.  8. 

Ortner:  Prag.  Ztschr.  f.  Heilk.,  1905,  p.  183. 

Passler:  Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  715. 

Passler  u.  Roily:  Deut.  Arch.  f.  klin.  Med.,  vol.  77,  p.  96. 

Roily:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42,  p.  283. 

Romberg  u.  Heinecke :  Deut.  Arch,  f .  klin.  Med.,  1901,  vol.  69,  p.  429. 


TREATMENT  OF  CIRCULATORY  FAILURE  311 

Romberg,  Passler,  Bruhns  u.  Miiller:  Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  652. 
Schmiedeberg  u.  Hans  Meyer:   Ztschr.  f.  physiol.  Chemie,  1879,  vol.  3,  p.  422. 
Schwartz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  54,  p.  135. 
Steyskal:     Ztschr.  f.  klin.  Med.,  1902,  vol.  367;  vol.  51,  p.  129. 

IN  CONDITIONS  OF  UNCOMPLICATED  VASCULAR  DEPRESSION  HO  benefit 

can  be  expected  from,  the  administration  of  cardiac  stimulants,  for 
such  can  result  only  if  the  tone  of  the  splanchnic  vessels  be  restored. 
If  this  be  done,  the  previously  insufficient  blood  flow  through  the 
vessels  of  the  skin,  muscles,  and  brain  becomes  sufficient  (v.  Basch, 
Biedl),  and,  the  heart  again  receiving  sufficient  amounts  of  blood, 
the  pressure  in  the  aorta  rises.  It  is  thus  that  sensory  reflexes  and 
centrally  acting  vasomotor  stimulants — for  example,  strychnine  and 
caffeine — may  favorably  influence  vascular  paresis.  On  the  other 
hand,  peripherally  acting  vasoconstricting  drugs,  such  as  epinephrin, 
may  similarly  alter  the  general  distribution  of  the  blood  in  spite  of 
the  existing  depression  of  the  vasomotor  centres. 

Sensory  Stimuli. — As  a  general  rule,  it  may  be  stated  that  a  very 
strong  sensory  stimulation  reflexly  lowers  the  blood-pressure,  while 
weaker  stimuli  raise  it.  The  effects  resulting  from  the  use  of  mus- 
tard plasters  and  baths  or  of  friction  with  skin  irritants,  etc.,  are  best 
explained  as  resulting  from  such  reflex  actions.  By  the  use  of  the 
plethysmograph  it  may  be  shown  that  the  kidney  volume  diminishes 
while  the  blood-vessels  are  more  completely  filled  and  the  blood- 
pressure  rises  under  the  influence  of  such  sensory  stimulation  (Wer- 
theimer,  Roy} . 

Strychnine  is  the  best  example  of  a  central  vasomotor  stimulant, 
its  action  on  the  circulation  being  a  partial  expression  of  its  action  on 
the  central  nervous  system.  Therapeutically  it  is  of  importance  that 
the  action  on  the  vasomotor  centres  develops  before  the  occurrence  of 
the  convulsive  symptoms.  In  this  stage  mild  sensory  stimuli,  such 
as  blowing  on  the  skin,  reflexly  cause  a  rise  in  blood-pressure  in  the 
rabbit.  However,  a  persistent  rise  in  the  blood-pressure  occurs  in  nor- 
mal animals  only  when  the  increased  reflex  excitability  of  the  motor 
centres  of  the  cord  is  fairly  evident  (Denis).  With  depressed  ex- 
citability of  the  central  nervous  system,  the  danger  of  causing  convul- 
sions is  much  lessened,  and  it  has  been  shown  that  strychnine  may 
improve  the  circulation  in  chloralized  animals  without  necessarily 
causing  convulsions.  These  actions  are  the  basis  for  the  adminis- 
ition  of  this  drug  in  acute  alcohol  or  chloral  poisoning,  as  also  in 

ther  conditions  with  similar  disturbances  of  the  circulation,  a  prac- 
tice much  more  common  in  other  countries  than  in  Germany.*  In 

England  and  America  a  direct  favorable  action  on  the  tone  of  the 
heart  muscle  is  attributed  to  strychnine,  and  recent  experiments  of 
Cameron  indicate  that  this  is  the  case. 

*  [Many  careful  clinicians  as  a  result  of  painstaking  investigation  of  the 
effects  of  strychnine  under  such  conditions  have  lost  their  faith  in  this  drug  as 
means  of  improving  the  circulation  in  infectious  disease. — TE.] 


312  PHARMACOLOGY  OF  CIRCULATION 

BIBLIOGRAPHY 

v.  Basch:  Ber.  d.  Sachs.  Akad.  d.  Wiss.,  1875,  vol.  27,  p.  373. 

Cameron,  cited  from  Hirschf elder :  Diseases  of  the  Heart  and  Aorta,  Philadelphia 

and  London,  1910,  p.  181. 

Denis:  Arch.  f.  exp.  Path.  u.  Pharm.,  1885,  vol.  20,  p.  306. 
Biedl  u.  Rainer:    Pfliiger's  Arch.,  1900,  vol.  79. 
Roy  and  Sherrington:  Journ.  of  Physiol.,  1890,  vol.  11,  p.  85. 
Wertheimer:  Arch,  de  Physiol.,  1893,  No.  2. 

Caffeine. — The  less  dangerous  caffeine  resembles  strychnine  in  its 
action  on  the  circulation,  but  never  increases  the  blood-pressure  to  so 
great  an  extent.  In  previous  sections  it  has  been  shown  that  caffeine 
also  is  a  stimulant  for  the  whole  central  nervous  system  (p.  25ff),  its 
vasomotor  actions  going  hand  in  hand  with  the  stimulation  of  the 
respiratory  centre  and  of  the  cerebral  function.  In  this  way  is  ex- 
plained the  fact  that  caffeine  is  one  of  the  most  useful  analeptics 
in  cases  where  the  circulatory  failure  results  from  depression  of  all 
the  functions  of  the  central  nervous  system. 

Experimentally  it  has  been  shown  that  the  vasomotor  excitability  in  dogs 
poisoned  by  alcohol  is  increased  under  the  influence  of  caffeine  and  that  the 
blood-pressure  returns  to  a  normal  height  after  moderate  doses  (Binz).  This 
return  of  reflex  excitability  may  also  be  well  observed  in  chloralized  rabbits, 
Passler  studied  the  actions  of  caffeine  on  the  depressed  circulation  of  infected 
rabbits,  and  found  that  subcutaneous  injections  of  caffeine-sodium  salicylate 
raised  the  lowered  blood-pressure  even  in  the  final  stages  of  pronounced  vasomotor 
depression.  Under  these  conditions  the  reflex  excitability  of  the  vasomotor 
centres  was  restored  or  improved,  and  this  favorable  action  persisted  for  a  con- 
siderable time — up  to  1%  hours. 

In  experiments  on  animals  it  may  be  shown  that  it  is  especially 
moderate  doses  of  caffeine  which  favorably  influence  the  blood-pres- 
sure, an  increase  of  the  dose  causing  further  rise,  and  very  large 
doses  or  rapid  intravenous  injection  being  followed  by  a  fall.  This  is 
due  to  the  depression  of  the  functional  power  of  the  heart  which 
undoubtedly  occurs  after  toxic  doses  of  caffeine.  The  discussion  of  the 
cardiac  action  of  caffeine  (see  pp.  267-8)  has  made  it  evident  that  under 
normal  conditions  it  produces  no  favorable  effects  on  the  performance 
of  the  heart,  and  that  after  large  doses  there  is  a  diminution  of  the 
amount  of  blood  expelled  by  the  heart  in  the  unit  of  time.  This  should 
soon  result  in  a  fall  of  the  arterial  pressure,  but  actually  this  remains 
high,  as  a  result  of  the  opposing  influence  of  the  vasoconstriction 
caused  by  the  drug  (Bock}.  Thus,  during  the  action  of  caffeine  we 
must  assume  that  increased  tone  of  the  splanchnic  vessels  occurs 
simultaneously  with  lessening  of  the  heart's  pumping  capacity. 

Further,  as  has  been  previously  mentioned,  caffeine  exerts  two 
actions,  each  of  which  tends  to  affect  the  frequency  of  the  pulse  in 
opposite  directions.  On  the  one  hand,  it  stimulates  the  vagus  centre 
and  slows  the  pulse  (Wagner,  Swirski,  Bock},  and  this  effect  appears 
to  be  the  predominant  one  resulting  from  therapeutic  doses  in  man 
(Riegel)  [?TR.].  Following  larger  doses,  on  the  other  hand,  the 


TREATMENT  OF  CIRCULATORY  FAILURE  313 

pulse  is  always  accelerated,  as  a  result  of  stimulation  of  the  accelerator 
terminations  in  the  heart.  It  is  possible  that  this  action  on  the 
motor  centres  in  the  heart  plays  a  more  important  role  in  patho- 
logical conditions.*  From  what  has  been  said,  an  increase  in  the 
blood-pressure  following  the  administration  of  caffeine  is  to  be  attrib- 
uted to  the  vasoconstriction  in  the  splanchnic  system  as  well  as  to  an 
increased  frequency  of  the  pulse  in  the  later  stages  of  its  action. 

Therapeutically  this  power  of  bringing  about  an  alteration  in  the 
distribution  of  the  blood  is  made  use  of  in  conditions  of  vascular 
depression.  It  is  possible,  too,  that  this  forcing  of  the  blood  out  of 
the  visceral  vessels,  as  well  as  direct  stimulation  of  the  cerebral  func- 
tion, accounts  for  the  use  of  the  various  beverages  containing  caffeine. 
The  effect  of  caffeine  in  overcoming  the  feeling  of  fatigue  after  eating 
may  be  due  to  the  action  of  caffeine  in  preventing  the  hyperaemia  of 
the  intestinal  vessels  which  usually  follows  the  ingestion  of  large 
amounts  of  food,  and  thus  preventing  the  relative  anaemia  of  the 
brain  which  accompanies  hyperaemia  of  the  portal  system.  The  in- 
creased blood  supply  to  the  skin  expresses  itself  as  a  subjective  feeling 
of  warmth  following  the  drinking  of  beverages  containing  caffeine. 

The  indirect  effect  on  the  heart  resulting  from  the  rise  in  blood- 
pressure  due  to  central  vasoconstrictor  stimulation  is  of  much  im- 
portance, for  under  the  influence  of  caffeine  the  constriction  of  the 
visceral  vessels  brings  larger  amounts  of  blood  to  the  right  heart, 
and  as  a  result  an  improvement  of  the  cardiac  function  occurs.  This 
is  quite  different  from  the  effects  in  the  heart-lung  circulation  (Bock, 
Bering),  where  the  systemic  vessels  have  been  eliminated  and  there- 
fore can  exert  no  influence  on  the  circulation.  [This  favorable  effect 
on  the  cardiac  function  is  still  further  augmented  by  the  peripherally 
induced  dilatation  of  the  coronary  vessels. — TR.]  Santesson  has  in 
indisputable  fashion  experimentally  demonstrated  an  indirect  im- 
provement of  the  cardiac  function  due  to  this  factor.  It  is  probable 
that  in  pathological  conditions  the  increase  of  the  absolute  power 
of  the  heart, — i.e.,  its  ability  to  overcome  a  greater  resistance — is  of 
importance.  A  weaker  heart  could  thus  better  meet  the  demands 
which  an  increase  of  the  blood-pressure  makes  upon  its  contractile 

Irgy. 

The  soluble  double  salts,  caffeine-sodium  benzoate  and  caffeine- 
sodium  salicylate,  are  used  as  circulatory  stimulants  in  preference  to 
the  pure  caffeine,  and  are  advantageously  administered  subcutaneously 
in  doses  of  0.2-0.5  gm.,  a  dosage  about  twice  as  large  as  that  of  pure 
caffeine.  Strong  black  coffee  is  also  much  used  in  conditions  of  col- 
lapse, in  narcotic  poisoning,  and  in  cases  of  threatening  cardiac 
weakness,  etc. 

*  fin  this  connection  the  reader  is  reminded  of  caffeine's  power  of  causing 
augmenting  extrasystoles    (p.  268). — TB.] 


314  PHARMACOLOGY  OF  CIRCULATION 

Pure  caffeine  (or  theine)  occurs  as  silky  shining  needles  of  somewhat  bitter 
taste.  It  is  soluble  in  water  in  the  proportion  of  1 :  50,  much  more  soluble  in 
hot  water  and  in  alcohol.  It  is  soluble  in  6  parts  of  chloroform,  by  the  use  of 
which  solvent  it  may  be  extracted  from  the  crude  drugs.  Its  chemical  composition 
is  that  of  a  trimethylxanthine.  Theobromine  and  theophyllin,  which  are  dimethyl- 
xanthines,  pharmacologically  closely  resembling  it,  are  discussed  elsewhere 
(see  p.  364). 

In  all  parts  of  the  earth,  plants  in  which  these  substances  occur  are  used 
for  beverages  or  as  stimulants.  A  cup  of  coffee  prepared  from  16  grammes  of 
roasted  beans  contains  about  0.1-0.12  gm.  of  caffeine.  The  same  amount,  with 
•some  theophyllin,  is  contained  in  an  infusion  made  from  5-6  gm.  of  dried  tea 
leaves.  Kola  nuts  (Kola  acuminata)  come  from  Africa,  while  cocoa,  which  con- 
iains  theobromine,  Paraguay  tea  (Ilex  paraguayensis ) ,  and  guarana  paste  (Paul- 
linia  sorbilis),  which  contains  especially  large  amounts  of  caffeine  and  which 
has  been  much  used  for  the  relief  of  headaches,  all  come  from.  America. 

Other  Constituents  of  Tea  and  Coffee. — Besides  caffeine,  by  all 
means  the  most  important  factor  in  producing  their  effects,  the  dif- 
ferent beverages  and  stimulants  of  this  group  contain  other  substances 
which  also  contribute  to  their  general  effects.  In  coffee,  substances 
with  aromatic  odor,  formed  during  the  roasting  from  legumin,  sugar, 
and  resins,  and  in  tea,  ethereal  oils  contained  in  the  leaves,  are  of 
some  physiological  significance.  These  beverages  owe  their  character- 
istic odor  and  taste  to  the  presence  of  these  substances,  which  also 
exert  some  action  on  the  central  nervous  system,  causing  an  increase 
in  the  frequency  of  respirations,  muscular  restlessness,  and  distinct 
psychic  stimulation.  The  so-called  caffeine-free  coffee,  from  which 
about  two-thirds  of  the  caffeine  has  been  removed  by  extraction  with 
benzol,  preserves  its  pleasant  flavor  while  the  stimulating  effects 
on  the  nervous  system  are  largely  lacking  (Harnack}. 

Other  Actions. — In  connection  with  the  general  picture  of  the 
•caffeine  action  the  reader  is  referred  to  the  action  on  the  cerebral 
function  (p.  25  ff.),  on  the  respiration  (p.  335),  on  the  renal  function 
(p.  360  ff.) ,  and  on  that  of  the  muscles.  Its  effects  on  the  body  temper- 
ature are  of  some  interest,  after  moderately  large  doses  the  temperature 
•sometimes  rising  0.5°  C.  and  after  toxic  doses  more  than  1°  C. 

Acute  poisoning  by  caffeine  has  been  observed  by  investigators  who 
intentionally  poisoned  themselves  and  after  immoderate  drinking  of 
leverages  containing  caffeine.  Conditions  of  tipsy  excitement,  sleep- 
lessness, vertigo,  and  muscular  tremors,  as  well  as  nausea  and  diar- 
rhoea, or  pronounced  frequency  of  micturition,  may  result  from  injec- 
tion of  0.5-0.6  gm.  After  injection  of  larger  doses  of  about  1.0  gm., 
in  addition  to  these  symptoms,  palpitation  and  irregularity  of  the 
heart,*  and  marked  increase  of  the  pulse  frequency,  with  a  feeling  of 
anxiety  and  at  times  some  of  the  symptoms  of  angina  pectoris,  may 
Arise  (Lehmann,  Curschmann) .  Usually  the  poisoning  passes  off 
gradually  without  any  serious  after  effects.  As  much  as  1.5  gm.  has 
teen  taken  by  rather  insusceptible  individuals  without  serious  results 
(v.  Frerichs). 

*  [Due  to  extrasystoles. — TR.] 


TREATMENT  OF  CIRCULATORY  FAILURE  315 

Only  a  small  part  of  the  caffeine  administered  is  excreted  un- 
changed in  the  urine  (Rost}  ;  another  portion  appears  in  the  urine, 
after  a  gradual  splitting  off  of  the  methyl  radicals,  as  monomethyl- 
xanthine  and  xanthine,  but  the  largest  portion  is  entirely  decomposed 
in  the  body.  The  dimethylxanthines  suffer  a  similar  loss  of  their 
methyl  radicals  (Bondzynski,  Albanese,  Kriiger). 

BIBLIOGRAPHY 

Albanese:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  35,  p.  449. 

Binz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1878,  vol.  9,  p.  31. 

Binz:  Zentralbl.  f.  klin.  Med.,  1900,  vol.  21,  No.  47. 

Bock:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  43,  p.  367. 

Bondzynski  u.  Gottlieb:   Ber.  d.  Chem.  Ges.,  1895,  vol.  28. 

Curschmann:  Deut.  Klin.,  1873,  p.  377. 

Cushny  u.  van  Naten:   Arch,  intern,  de  Pharmacodyn.,  1901,  vol.  9,  p.  169. 

v.  Frerichs:   Wagner's  Handwb'rterbuch  d.  Physiol.,   Braunschweig,   1853,  vol.   3, 

p.  721. 

Harnack:   Deut.  med.  Woch.,  1908,  No.  45. 

Kriiger  u.  Schmidt:   Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45,  p.  259. 
Kriiger  u.  Schmidt:   Ber.  d.  deut.  Ges.,  1899.  vol.  32. 
Lehmann,  K.  B. :   Arch.  f.  Hygiene,  1898,  vol.  32,  p.  310. 
Passler:   Deut.  Arch.  f.  klin.  Med.,  vol.  64,  p.  715. 
Hiegel:  Kongr.  f.  inn.  Med.,  1884. 

Host:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36,  p.  56. 
Santesson:   Skand.  Arch.  f.  Physiol.,  1901,  vol.  12,  p.  259. 
Swirski:   Pfltiger's  Arch.,  1904,  vol.  103. 
Wagner:  Diss.,  Berlin,  1885. 

Camphor  is  another  drug  used  for  its  effects  on  the  arteries. 
On  page  274  it  has  been  stated  that  this  drug  brings  about  changes  in 
the  distribution  of  the  blood  and  in  the  blood-pressure  by  stimulation 
of  the  vasomotor  centres,  but  these  effects  are  obtained  in  normal 
animals  only  by  the  administration  of  doses  large  enough  to  cause 
convulsions.  In  man,  however,  the  doses  usually  are  much  smaller 
than  those  which  cause  convulsions,  and  yet  it  is  certain  that  the 
subcutaneous  injection  of  0.1-0.4  gm.  of  camphor  frequently  improves 
the  circulation,  though  often  only  temporarily,  even  when  the  patient 
is  in  extremis.  In  accordance  with  this  are  Passler 's  observations  of 
the  distinct  improvement  of  the  vasomotor  function  which  followed  the 

K'ection  of  camphor  in  infected  animals  (( ?)  Translator's  note,  p.  316) . 
This  suggests  that  perhaps  camphor  produces  more  marked  effects 
the  functions  of  these  centres  when  they  are  depressed  than  under 
rmal  conditions.     It  has  often  been  observed  that  when  the  tone 
of  the  centres  is  diminished  they  react  to  smaller  doses  of  stimulating 
substances  than  when  they  are  functioning  optimally,  somewhat  as  a 
string  may  be  stretched  by  less  power  if  its  tension  has  been  previously 
diminished. 

Thus  far  this  fact,  of  equal  practical  and  therapeutic  importance,  is  not 
thoroughly  understood.  In  a  similar  fashion  the  central  innervation  of  muscular 
movements  is  distinctly  stimulated  by  alcohol  or  caffeine  if  these  be  administered 
in  conditions  of  fatigue  (Frey,  Joteyko),  although  the  normal  muscle  innervation 
is  not  measurably  influenced  by  similar  doses,  and  the  same  is  true  of  the  action 


316  PHARMACOLOGY  OF  CIRCULATION 

of  similar  doses  of  alcohol  on  the  respiratory  centre  (Wendelstadt ).  By  such 
analogy  it  may,  therefore,  be  possible  to  explain  the  fact  that  certain  drugs 
improve  the  depressed  function  of  the  vasomotor  centres,  even  though  the  optimal 
normal  function  is  uninfluenced  by  equal  doses. 

In  addition,  the  results  of  stimulation  of  the  vasomotor  centres 
are  much  more  apparent  in  pathological  conditions  of  the  circulation 
than  in  conditions  of  health,  for  moderate  vasoconstriction  causes  in 
the  healthy  animal  only  an  alteration  in  the  distribution  of  the  blood, 
and,  on  account  of  the  normal  compensatory  regulations,  the  blood- 
pressure  need  not  rise.  If,  on  the  other  hand,  in  pathological  con- 
ditions of  the  circulation  this  compensatory  regulation  is  disturbed 
and  the  portal  vessels  dilated,  these  drugs  stimulating  the  vasomotor 
centres  cause  constriction  of  the  abdominal  vessels  and  bring  about  a 
normal  distribution  of  the  blood  once  more,  and  thus  the  previously 
lowered  blood-pressure  is  raised. 

[Heard  (Am.  Jour,  of  Med.  Sci.,  1913,  vol.  135,  p.  238)  has  recently 
observed  a  number  of  patients  suffering  from  various  diseases,  to  whom 
camphor  was  administered  hypodermatically.  He  reports  that  doses 
ranging  from-  small  doses  of  a  few  grains  up  to  as  much  as  fifty  grains, 
produced  no  definite  effects  on  the  circulation.  They  also  failed  to 
favorably  influence  auricular  fibrillation. — TR.] 

BIBLIOGRAPHY 

Frey:  Mitteil.  d.  Schweitz.  Klin.,  1896,  series  4,  No.  1. 
Joteyko:  Trav.  Solvay,  1904,  vol.  6. 
Piissler:   Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  715. 
Wendelstadt:  Pfliiger's  Arch.,  1899,  vol.  76,  p.  223. 

Alcohol. — It  is  proper  to  consider  from  this  point  of  view  the 
often  repeated  experience  of  the  favorable  effects  of  small  doses  of 
alcohol  in  circulatory  failure.  Kunkel  states  that  "the  unpre- 
judiced observation  of  physicians  permits  no  other  conclusion 
than  that  alcohol,  at  least  in  certain  pathological  conditions,  exerts 
a  favorable  influence  on  the  depressed  cardiac  and  respiratory  func- 
tions. A  few  spoonfuls  of  a  good  wine  administered  to  a  patient 
in  profound  collapse,  with  scarcely  perceptible  pulse  and  hardly 
perceptible  respiration,  and  pallid  cold  face,  often,  after  a  few  min- 
utes, cause  color  to  reappear  in  the  cheeks,  as  the  pulse  becomes  fuller 
and  the  respirations  deeper  and  more  regular."  On  the  other  hand, 
there  are  many  who  deny  these  favorable  effects.  The  stimulation 
of  the  respiratory  centre,  especially  in  conditions  of  fatigue,  has  been 
experimentally  proved  (see  p.  47).  If,  as  seems  to  be  the  case,  alcohol 
under  certain  conditions  favorably  influences  the  circulation,  this, 
according  to  our  present  knowledge,  is  to  be  attributed  in  part  to  its 
action  on  the  heart,  and  in  part  to  its  vasomotor  actions.  On  page  259 
it  has  been  stated  that  recent  experimental  investigations  have  demon- 
strated that  alcohol  may  bring  about  an  improvement  of  the  circula- 
tion, especially  if  the  heart  action  be  enfeebled. 


317 

The  cutaneous  vessels  dilate  even  after  small  doses  of  alcohol,  as 
a  result  of  the  diminution  of  their  tone,  but  at  the  same  time  the 
pressure  in  the  aorta  rises  somewhat.  This  alone  renders  it  probable 
that  other  vascular  systems  must  be  contracted  during  the  action 
of  the  alcohol,  and,  in  fact,  alcohol  appears  to  constrict  the  visceral 
vessels,  Dixon,  by  the  use  of  the  plethysmograph,  having  recently 
shown  that  the  constriction  of  the  intestinal  vessels  occurs  coinei- 
dently  with  the  rise  in  blood-pressure.  According  to  this  author,  the 
splanchnic  vasoconstriction  is  in  part  the  result  of  an  action  on  the 
centres,  and  it  is  this  portion  of  the  pharmacological  action  of  alcohol 
which  may  perhaps  be  of  value  in  conditions  of  circulatory  failure. 
However,  it  is"  certain  that  the  vasoconstriction  is  in  part  due  to 
peripheral  actions,  for  it  occurs  even  after  the  elimination  of  the 
vasomotor  centres  (Kochmann,  Wood  and  Hoyt). 

In  this  way  alcohol  alters,  the  distribution  of  the  blood  by  forcing 
it  from  the  abdominal  viscera  and  at  the  same  time  by  dilating  the 
peripheral  vessels.  As1  a  result  of  the  preponderance  of  the  vaso- 
constriction, there  is  an  improvement  of  the  circulation,  especially 
if  the  blood-pressure  were  previously  abnormally  low,  and  in  this 
way  the  blood  flow  through  the  heart  is  indirectly  improved.  In  man, 
too,  it  is  possible  to  demonstrate  a  rise  in  blood-pressure  after  small 
doses  of  60-80  c.c.  of  10  per  cent,  alcohol  or  wine  (Binz). 

BIBLIOGRAPHY 

Bachem:  Arch,  intern,  de  Pharmacodyn.,  1905,  vol.  14,  p.  437. 

Binz:   Ther.  d.  Gegenw.,  January,   1899. 

Dixon:  Journ.  of  Physiol.,  1907,  vol.  35. 

Haskovec:   Arch,  de  m6d.  exp.,  1901,  vol.  13,  p.  539. 

Kochmann:   Arch,  intern,  de  Pharmacodyn.,  1904,  vol.  13,  p.  329. 

Kunkel:  Handb.  d.  Toxikol.,  1901,  p.  408. 

Wood  and  Hoyt:  Mem.  of  the  Nat.  Sciences,  Washington,  1905,  vol.  10. 

Ether. — Next  to  camphor,  ether  is  the  drug  most  often  used  as 
an  analeptic  in  conditions  of  failing  circulation.  The  reflexes  due  to 
the  sensory  irritation  at  the  place  of  application  were  formerly 
considered  to  be  alone  responsible  for  the  favorable  effect  on  the 
circulation  which  followed  its  subcutaneous  injection  or  its  internal 
administration  (Hoffmann's  anodyne  in  fainting).  Recently  Derou- 
aux,  using  plethysmographic  methods,  found  that  small  doses  of 
ether,  just  as  is  the  case  with  alcohol,  carried  by  the  blood  to  the 
internal  organs  caused  a  vasoconstriction,  so  that  under  some  cir- 
cumstances the  blood-pressure  may  rise  considerably.  This  is  espe- 
cially the  case  if  the  blood-pressure  was  previously  abnormally  low. 
On  the  other  hand,  it  has  not  been  possible  to  demonstrate  that  ether 
exerts  a  favorable  action  on  the  isolated  heart,  although,  according 
to  Derouaux,  the  heart  beating  in  the  intact  circulation  beats  more 
powerfully  and  rapidly  while  the  blood-pressure  is  raised.  This  effect 
on  the  heart  is,  therefore,  to  be  considered  as  the  result  of  the 


318  PHARMACOLOGY  OF  CIRCULATION 

better  blood  flow  through  the  coronary  vessels.  The  analeptic  effects 
of  ether,  which  have  always  been  claimed  by  physicians,  should, 
accordingly,  be  attributed  to  the  improvement  of  the  distribution  of 
the  blood  resulting  from  stimulation  of  the  vasomotor  centres  [and 
in  addition  to  the  local  constricting  effect  on  the  splanchnic  vessels. — 
TR.]  as  well  as  to  its  stimulant  action  on  the  respiratory  centre. 

BIBLIOGRAPHY 
Derouaux:  Arch,  intern,  de  Pharmacodyn.,  1909,  vol.  19. 

Saline  Infusions. — It  is  possible  in  still  another  fashion  to  help  a 
circulation  which  is  failing  as  a  result  of  vasoparesis.  By  increasing 
the  volume  of  blood  it  is  possible,  for  a  time,  to  obtain  the  desired 
better  supply  of  blood  to  the  nervous  system  and  to  the  heart.  An 
internal  hemorrhage,  as  it  were,  results  from  the  relaxation  of  the 
splanchnic  vessels,  the  total  cross-section  of  the  vascular  tree  thus 
becoming  too  large  for  the  amount  of  blood  present  in  the  body.  In 
such  case  the  necessary  rapidity  of  blood  flow  through  the  vital 
organs  may  be  secured  by  a  better  filling  of  the  vascular  systems  as 
well  as  by  a  constriction  of  the  dilated  vessels.  In  place  of  the  dan- 
gerous transfusion  of  blood  (often  resulting  in  hasmoglobinuria, 
damage  to  the  kidneys,  etc. ) ,  subcutaneous  or  intravenous  infusion  of 
indifferent  isotonic  salt  solutions  may  be  employed  for  this  purpose. 
Of  these  the  alkaline  Ringer's  solution  which  contains  calcium  is  the 
best.  [Direct  arm  to  arm  transfusion,  especially  advocated  by  Crttef 
has  many  advantages,  but  for  obvious  reasons  it  is  not  always  avail- 
able.—TR.] 

If  the  vascular  tone  be  normal,  such  an  artificial  increase  in  the 
contents  of  the  vessels  will  be  removed  from  the  circulation  extremely 
rapidly,  as  was  shown  long  ago  by  the  experiments  of  Cohnheim  and 
Lichtheim.  If,  however,  the  blood-pressure  be  low,  the  salt  solution 
passes  from  the  vessels  into  the  tissues  and  the  urine  much  more 
slowly  and  remains  in  the  blood  for  a  considerable  period.  When 
the  splanchnic  innervation  is  functioning  normally,  the  splanchnic 
vessels  are  able  to  take  up  considerable  excess  of  fluid,  and,  therefore, 
under  normal  conditions  the  blood-pressure  is  not  markedly  raised  by 
saline  infusions,  even  during  the  period  in  which  the  solutions  intro- 
duced have  not  yet  been  removed  from  the  blood.  If,  on  the  other 
hand,  the  splanchnic  system  is  already  overfilled  as  a  result  of  vaso- 
motor depression,  its  capacity  for  absorbing  more  fluid  is  lessened,  and 
thus  the  introduction  of  even  moderate  amounts  of  fluid  markedly 
raises  the  blood-pressure  and  thus  brings  about  an  improvement  of  the 
depressed  circulation  (Pdssler). 

In  such  fashion  saline  infusions  may  act  favorably  in  the  de- 
pressed circulation  of  infectious  diseases,  and  also  by  "washing  out" 
various  toxins  and  other  poisonous  substances  (Dastre,  Sahli,  Bosc, 
Lenhartz)  so  far  as  these  are  not  firmly  combined  with  the  tissues, — 


TREATMENT  OF  CIRCULATORY  FAILURE  319- 

for  example,  diphtheria  toxin  (Enriques).  In  case  the  body  has  lost 
large  amounts  of  water,  as  in  cholera  and  cholera  morbus,  infusions 
also  counteract  the  dehydration  of  the  tissues.  It  is  to  be  remembered, 
however,  that  saline  infusions  can  be  of  permanent  value  only  in- 
directly (by  favoring  the  excretion  of  poisonous  substances,  etc.), 
for  the  vasomotor  centres  remain  depressed,  notwithstanding  the  better 
filling  of  the  vascular  system,  so  that,  in  spite  of  the  fact  that  the 
blood-pressure  is  raised  by  the  infusion,  if  the  experimental  infection 
be  a  grave  one,  sensory  stimuli  remain  ineffective  so  long  as  the  toxines 
causing  the  vascular  paresis  continue  to  be  produced  (Passler). 

The  conditions  are  much  more  favorable  for  the  life-saving  action 
of  infusions  in  cases  where  death  is  threatened  from  hemorrhage. 
Goltz  was  the  first  to  assert  that  death  after  extensive  hemorrhage 
at  times  occurred  not  because  the  amount  of  blood  remaining  was 
insufficient  to  maintain  the  internal  respiration  of  the  tissues,  but 
because  it  was  not  sufficient  to  maintain  the  circulation.  In  true 
hemorrhage,  just  as  in  the  so-called  "bleeding"  into  the  splanchnic 
system,  the  first  endeavor  of  the  organism  is  to  supply  sufficient  blood 
to  the  vital  organs  by  compensatorily  constricting  the  vessels  of  the 
skin  and  muscles.  If  this  regulatory  mechanism  and  the  inflow  of  fluid 
from  the  tissues  into  the  blood  are  not  sufficient  to  bring  about  a. 
sufficient  flow  of  blood  into  the  heart,  cardiac  weakness  results  just  as 
in  the  case  of  paralysis  of  the  vessels. 

Hardly  any  other  symptomatic  therapeutic  effects  may  be  better 
demonstrated  than  the  reviving  effect  of  saline  infusion  after  an 
animal  has  been  bled  until  respiration  ceases  and  the  pulse  disappears. 

The  experimental  proof  that  saline  infusions  may  save  life  after  otherwise- 
fatal  hemorrhage  was  first  attempted  in  experiments  on  dogs.  Here,  however, 
it  was  found  to  be  difficult  to  estimate  the  amount  of  blood  in  the  individual 
animals,  for  this  varies  within  considerable  limits.  Loss  of  blood  in  amounts 
less  than  4.6  per  cent,  of  the  body  weight  are,  as  a  rule,  well  borne,  even  without 
infusion,  while  if  the  blood  loss  exceeds  5.1-5.4  per  cent.,  death  usually  ensues. 
However,  the  majority  of  the'  more  recent  observers  are  of  the  opinion  that  when 
hemorrhage  reaches  this  amount  infusions  are  no  longer  able  to  preserve  life 
permanently,  but  that  in  spite  of  temporary  success  the  dogs  die  later  as  a  result 
of  the  loss  of  haemoglobin  ( Maydl,  Schramm,  Feis ) .  However,  there  is  no  doubt 
that  infusions  regularly  bring  about  rapid  recovery  in  our  experimental  animals 
after  hemorrhage,  even  if  before  the  infusion  the  respiration  has  ceased,  the  reflex 
excitability  has  disappeared,  and  the  heart  beats  have  become  unrecognizable 
(Kronecker) . 

According  to  all  clinical  experience,  it  appears  that  in  man  infu- 
sions have  a  greater  life-saving  power  than  in  our  laboratory  animals 
(Scliwarz,  Sclwnborn,  Kuttner,  Laufer}.  This  difference  between 
clinical  experience  and  the  results  obtained  from  animal  experimenta- 
tion is  probably  due  to  the  fact  that  the  human  vascular  system,  espe- 
cially after  severe  operations  (chloroform  narcosis),  is  not  capable  of 
adapting  itself  to  large  blood  losses  to  so  great  a  degree  as  is  the 
vascular  system  of  our  laboratory  animals.  As  a  result,  exsan- 
guinated men  are  much  more  likely  to  die  from  the  mechanical 


320  PHARMACOLOGY  OF  CIRCULATION 

results  of  hemorrhage  than  are  the  latter  (Leichtenstern) .  In  the 
dog,  for  example,  on  account  of  the  completeness  with  which  the 
regulatory  constriction  of  the  splanchnic  system  compensates  for 
hemorrhage,  cessation  of  the  respiration  and  disappearance  of  the 
pulse  occur  only  when  the  bleeding  is  so  great  that  it  necessarily 
will  result  fatally  on  account  of  the  loss  of  the  red  cells,  while  in 
man  collapse  appears  to  develop  after  much  less  severe  hemorrhage. 
For  the  significance  of  transfusion  in  replacing  blood-cells  lost  by  hem- 
orrhage or  otherwise  rendered  useless,  see  page  435. 

BIBLIOGRAPHY 

Bosc  et  Vedel:  Compt.  rend.  Soc.  de  Biol.,  1896. 

Dastre  et  Loye:   Arch,  de  Physiol.,  1889,  p.  253. 

Enriques  et  Hallion:   Compt.  rend.  Soc.  de  Biol.,  1896,  p.  756. 

Feis:   Virchow's  Arch.,  1894,  vol.  138,  p.  75. 

Goltz:   Virchow's  Arch.,  1864,  vol.  29. 

Kronecker  u.  Sander:   Berl.  klin.  Woch.,  1879,  p.  768. 

Kronecker  u.  Sander:   Korrespondenzblatt  f.  Schweiz.  Arzte,  1886,  Nos.  16-18, 

Kuttner:  Beitrag  f.  klin.  Chir.,  1903,  vol.  40,  p.  609. 

Laufer:   Zentralbl.  f.  d.  Grenzgebiet  d.  Med.  u.  Chir.,  1900,  p.  422. 

Leichenstern :  Volkmann's  Vortr.,  1890-94,  No.  25. 

Lenhartz:   Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  189. 

Maydl:  Wien.  med.  Jahrbuch,  1884,  No.  1. 

Passler:  Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  715. 

Sahli:  Volkmann's  Vortrage,  1890-94,  No.  11. 

Schonborn:   Handbuch  d.  spez.  Path.  u.  Ther.,  Jena,  1895,  vol.  2,  p.  3. 

Schramm:   Wien.  med.  Jahrbuch,  1885. 

Schwarz:  Habilitations-Schrift,  Halle,  1881. 

Epinephrin. — The  most  efficient  means  for  the  rapid  restoration  of 
the  circulation  in  all  conditions  of  vascular  depression  is  the  intra- 
venous injection  of  epinephrin.  This  aids  the  halting  circulation 
in  another  way  than  do  the  above  discussed  vasomotor  drugs,  for  it 
constricts  the  arterial  path  by  acting  locally  on  the  vessel  walls  (p.  279) , 
and  is  able  to  restore  the  tone  of  the  splanchnic  vessels  even  after 
they  have  been  completely  relaxed  as  a  result  of  vasoparesis  of  central 
origin.  In  this  way,  in  spite  of  the  persisting  paralysis  of  the  vaso- 
motor centres,  the  abnormal  distribution  of  the  blood  is  changed 
back  to  the  normal  so  long  as  the  epinephrin  action  lasts,  for  central 
stimulation  of  the  vessels  is  replaced  for  the  time  being  by  an 
increased  peripheral  stimulation.  As  this  drug  is  at  the  same  time  a 
powerful  stimulant  for  the  heart's  action,  it  would  be  the  ideal 
drug  for  combating  circulatory  failure  if  its  action  were  not  so 
fleeting.  However,  its  good  effects  appear  to  last  especially  long 
when  it  is  used  in  cases  of  circulatory  failure. 

The  revival  by  epinephrin  of  hearts  poisoned  by  chloroform  and 
potassium  was  demonstrated  experimentally  a  good  while  ago  (Gott- 
lieb). More  recently  it  has  been  shown  that  animals  dying  as  a 
result  of  poisoning  by  diphtheria  toxin,  with  a  blood-pressure  as  low 
as  30-40  mm.  Hg,  may  be  kept  alive  for  as  long  as  7  hours  if  this 
drug  be  administered  intravenously,  the  blood-pressure  remaining  at 


TREATMENT  OF  CIRCULATORY  FAILURE  321 

a  normal  height  for  as  long  as  30-40  minutes  after  a  single  injection 
(Fr.  Meyer).  The  respiration  improves  and  the  reflexes  return,  while 
the  weak  and  very  slow  pulse  becomes  strong  and  rapid.  The  drug's 
actions  on  both  the  heart  and  the  vessels  appear  to  be  involved  in  this 
astonishingly  successful  experimental  therapy.  In  consequence  of  the 
narrowing  of  the  blood  path,  the  rapidity  of  the  blood  flow  is  in- 
creased and  the  heart  receives  again  the  normal  quantities  of  blood, 
while  the  ability  of  the  heart  to  do  this,  in  spite  of  the  extensive 
damage  done  to  it  by  the  diphtheria  toxin,  is  doubtless  due  to  the 
direct  action  of  the  epinephrin  in  causing  a  strengthening  of  the 
contractions  and  an  increase  in  their  rate. 

In  all  cases  of  central  vascular  depression  (e.g.,  poisoning  by 
chloral  hydrate,  by  depressing  diphtheria  toxins,  etc.)  or  of  peripheral 
paralysis  of  the  splanchnic  system  (e.g.,  acute  arsenic  poisoning),  in 
experiments  on  animals,  epinephrin  will  bring  the  blood-pressure  back 
again  to  the  normal,  although  it  may  previously  have  fallen  nearly  to 
zero. 

Clinically,  intravenous  injections  of  epinephrin  were  first  tried 
by  L.  Heidenhain,  who  used  it  in  combination  with  saline  infusions 
in  the  circulatory  failure  of  severe  general  peritonitis.  [Crile,  of 
Cleveland,  recommended  and  used  such  injections  in  the  treat- 
ment of  shock  and  other  conditions  of  collapse  considerably  earlier 
than  the  above-mentioned  author. — TR.]  In  such  conditions  (perito- 
nitis) the  pathological  distribution  of  the  blood  results  from  the 
inflammatory,  hyperaemia  of  the  mesenteric  and  peritoneal  vessels,  and, 
according  to  Heinecke,  also  from  a  depression  of  the  vasomotor  centres 
by  bacterial  toxins.  According  to  Heidenhain' 's  frequently  corrob- 
orated experiences,  this  "internal  hemorrhage"  due  to  vascular  de- 
pression may  often  be  combated  with  striking  success  by  the  slow 
injection  of  about  %  mg.  of  epinephrin  in  %-l  litre  of  physiological 
saline  solution  heated  to  the  temperature  of  the  body.  In  cases  in 
hich  the  patient  is  still  able  to  overcome  the  infection,  this  procedure 

y  be  a  life-saving  one. 

Kothe's  recommendation  to  add  epinephrin  to  the  fluid  infused  in 
of  threatening  death  from  hemorrhage  is  quite  as  rational,  for 
.us  not  only  are  the  vessels  better  filled,  but  in  addition  their  tone 
is  improved.  In  accordance  with  the  facts  first  observed  experimen- 
tally, such  experience  of  its  use  in  man,  as  is  at  present  available, 
has  shown  that  these  intravenous  injections  exert  a  powerful  reviving 
influence  in  every  form  of  collapse  of  the  circulation.  Thus,  Kothe 
by  intravenous  injection  of  %-l  mg.  of  epinephrin  was  able  to  revive 
patients  who,  following  spinal  anaesthesia,  were  moribund,  without 
perceptible  heart  beat  and  with  abolished  cornea!  reflexes  and  inter- 
rupted respiration,  as  well  as  cases  of  severe  post-operative  shock. 
The  heart  action  improved  immediately,  and  after  a  few  seconds  the 
>ulse  could  again  be  felt,  and  the  respiration  and  other  functions  of 
21 


322  PHARMACOLOGY  OF  CIRCULATION 

the  nervous  system  gradually  returned  to  normal.  Eecently,  John 
has  reported  favorable  results  from  this  procedure  in  most  severe 
circulatory  collapse  in  the  course  of  pneumonia,  septicaemia,  etc.  Even 
when  all  other  analeptics  (strophanthin  intravenously  injected,  caf- 
feine, camphor,  etc.)  had  failed,  the  threatening  cardiac  weakness 
was  at  once  relieved  by  %-l  mg.  of  epinephrin,  and  often  permanent 
life-saving  results  were  obtained. 

In  all  such  cases  in  which  epinephrin  is  injected,  the  immediate 
strengthening  of  even  a  most  alarmingly  weakened  heart  action  indi- 
cates that  the  direct  action  on  the  heart  cooperates  with  the  vasocon- 
stricting  action,  and  this  improvement  of  the  circulation  then  brings 
about  an  improvement  in  the  vitally  important  functions  of  the  central 
nervous  system.  The  extent  to  which  such  results  may  succeed  in  pre- 
serving life  depends  on  whether  the  cause  of  the  circulatory  failure — 
for  example,  the  vascular  depression — still  persists  or  whether,  as  in 
shock  or  chloroform  poisoning,  the  circulation  needs  support  for  only 
a  short  critical  period.  No  good  can  result  from  increasing  the  size 
of  the  dose  injected  at  one  time,  but,  on  the  contrary,  too  large  doses, 
by  causing  too  great  a  rise  in  the  blood-pressure,  are  dangerous  to  a 
heart  already  overtaxed  to  its  limit  of  endurance.*  On  the  other  hand, 
repeated  injection  of  small  doses  is  well  borne.  When  one  considers 
how  fleeting  is  the  effect  of  epinephrin  in  experiments  on  animals, 
the  long  duration  of  the  effect  produced  by  a  single  injection  in  man 
under  these  pathological  conditions  is  very  striking,  the  improvement 
in  the  circulation  lasting  sometimes  6-8  hours  and  longer.  It  is 
probable  that  this  is  the  result  of  the  favorable  effect  on  the  vasomotor 
centres,  they  receiving  for  a  time  sufficient  amounts  of  blood  which 
thus  favor  their  restoration  to  more  normal  function. 

Very  recently  the  subcutaneous  injection  of  epinephrin  has  been  tried  in 
the  treatment  of  circulatory  failure,  large  doses  (up  to  6-10  mg.)  being  given. 
[The  translator  has  seen  the  subcutaneous  injection  of  1  to  1.5  mg.  followed  by  a 
very  alarming  rise  in  the  blood-pressure  and  a  whole  clinical  picture  resembling 
closely  the  results  of  intravenous  administration  of  large  doses  to  animals.  He, 
therefore,  believes  it  proper  to  warn  against  the  subcutaneous  injection  of  large 
amounts. — Tu.].  However,  this  method  of  administration  seems  less  rational  than 
intravenous  administration,  inasmuch  as  epinephrin,  by  its  local  vasoconstricting 
action,  prevents  its  rapid  absorption,  and  therefore  must  remain  inactive  in  the 
subcutaneous  tissues.  [Although,  a  priori,  this  would  be  expected,  it  has  been 
indisputably  shown  that  in  man  subcutaneous  injections  of  epinephrin  produce 
very  distinct  effects,  and  many  clinical  observations  would  indicate  that  ita 
subcutaneous  injection  is  frequently  followed  by  more  or  less  lasting  improvement 
of  the  circulation. — TK.] 

BIBLIOGRAPHY 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  38,  p.  99. 
Heidenhain,  L.:    Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1908,  vol.  18,  p.  837. 
Heinecke:    Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  69,  p.  429. 
John:   Miinchn.  med.  Woch.,  1909,  No.  24. 

*  [In  the  laboratory  such  large  doses  appear  at  times  to  cause  fibrillation  of  the 
ventricle.  Consequently  care  should  be  taken  not  to  give  too  large  doses. — TR.] 


TREATMENT  OF  CIRCULATORY  FAILURE  323 

Kothe:  Ther.  d.  Gegenw..  February.  1909. 

Kothe:   Zentralbl.  f.  Chir.,  1907,  No.  33. 

Meyer,  Fr.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60,  p.  208. 

Winter:  Wien.  klin.  Woch.,  1905,  No.  20. 

Digitalis  Group. — A  lasting  improvement  in  the  distribution  of  the 
blood  might  be  expected  to  result  from  the  constriction  of  the  intes- 
tinal vessels  which  follows  the  administration  of  the  members  of  the 
digitalis  group.  Experimentally  it  is  possible  by  their  use  to  raise  the 
blood-pressure  of  infected  animals — for  example,  in  diphtheria 
(Passler,  Meyer] — and  it  is  not  impossible  that  the  successful  results  of 
the  intravenous  injection  of  strophanthin  in  conditions  of  collapse  of 
the  circulation  are  at  least  partly'  due  to  the  vasoconstriction  which 
this  drug  induces  (see  p.  306).* 

BIBLIOGRAPHY 

Meyer,  Fr.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60,  p.  208. 
Passler:  Deut.  Arch.  f.  klin.  Med.,  1899,  vol.  64,  p.  715. 

TREATMENT  OF  VASCULAR  CRISES  AND  VASOCONSTRICTION 

Without  doubt  tonic  vasoconstriction  plays  an  important,  but  as 
yet  insufficiently  understood,  role  in  pathology.  General  contraction 
of  the  vessels  and  vasoconstriction  in  special  regions  must  be  separately 
considered.  Of  the  general  vasoconstrictions  only  those  due  to  toxic 
agents  are  at  all  well  understood.  They  may  result  from  a  stimulation 
of  all  the  vasomotor  centres,  as,  for  example,  in  asphyxia  or  in  strych- 
nine poisoning,  or  they  may  be  due  to  a  more  or  less  general,  peripher- 
ally caused  vasoconstriction  such  as  that  following  the  intravenous 
injection  of  epinephrin. 

Both  types  also  occur  as  endogenous  pathological  phenomena. 
Thus,  the  accumulation  of  carbonic  acid  in  the  blood,  which  results 
from  insufficient  arterialization,  causes  an  over-excitability  of  the 
vasomotor  centres,  and  this  is  probably  the  chief  cause  of  the  rise  in 
blood-pressure  observed  in  conditions  of  stasis  [in  combination  with 
the  increase  of  viscosity  due  to  the  excess  of  carbon  dioxide. — TR.]. 
A  general  increase  in  the  peripheral  vascular  tone  may,  on  the  other 
hand,  be  due  to  a  too  free  secretion  of  epinephrin  in  cases  in  which 
the  inner  secretion  of  the  adrenal  glands  is  pathologically  disturbed. 
[This  has  been  asserted  to  be  the  cause  of  the  commonly  observed 
hypertension  of  Bright 's  disease,  but  this  view  has  also  been  stren- 
uously combated.  At  present  we  are  not  in  a  position  to  state  the 
cause  of  this  hypertension,  but  can  simply  attribute  it  to  an  increased 
general  vascular  tone. — TR.]  Finally,  the  vasomotor  centres  are  sus- 
ceptible to  manifold  reflex  influences  and  thus  may  be  pathologically 
influenced  by  various  distant  organs. 

*  Crile's  observations  on  dogs  in  shock  indicate  that  members  of  the  digitalis 
group  are  not  helpful,  but,  on  the  contrary,  are  actually  harmful  in  shock. 


324  PHARMACOLOGY  OF  CIRCULATION 

A  general  increase  of  the  vascular  tonus  has,  as  its  first  result, 
an  alteration  of  the  distribution  of  the  blood,  for  all  vascular  systems 
are  not  equally  constricted,  the  vessels  in  the  splanchnic  system  being 
more  affected  than  the  others.  The  vessels  of  the  skin  and  muscles 
by  active  dilatation  serve  a  regulating  purpose,  while  other  vascular 
systems,  such  as  that  of  the  brain  and  that  of  the  lungs,  in  a  more  pas- 
sive fashion  adapt  themselves  to  take  up  the  blood  squeezed  out 
from  the  abdominal  viscera.  Overfilling  of  the  brain  with  blood  may 
therefore  result  from  an  insufficiently  compensated  vasoeonstriction 
in  the  splanchnic  system,  and  the  insomnia  of  many  individuals  in 
high  altitudes  may  be  due  to  such  moderate  disturbances,  for  a  high 
altitude  causes  an  increase  in  the  general  vascular  tone.  Such  disturb- 
ances in  this  compensatory  regulation  occur  particularly  in  arterio- 
sclerosis, Rombcrg  and  O.  Mutter  having  shown  that  the  vessels  in  the 
extremities  react  with  increasing  lack  of  promptness  to  the  reflex 
action  of  heat  and  cold  as  the  arteriosclerosis  progresses.  Vascular 
crises,  therefore,  are  not  so  readily  compensated  for  in  arteriosclerotie 
patients  as  in  normal  individuals. 

Marked  constriction  of  the  splanchnic  vessels — for  example,  that 
occurring  in  strychnine  poisoning  or  in  asphyxia — produces  secondary 
effects  on  the  heart,  if  the  blood  does  not  find  sufficient  accommodation 
in  other  regions,  the  pressure  in  the  aorta  rising  and  the  blood 
accumulating  in  the  heart  and  in  the  pulmonary  circulation  ( Waller] . 
For  these  reasons  it  is  clear  that  extensive  vasoconstrietion  may  cause 
a  diminution  of  the  pulse  volume  of  the  left  heart, — i.e.,  a  relative  or 
absolute  insufficiency  of  the  heart, — and  under  these  conditions  vaso- 
dilating  agents  may  indirectly  improve  the  cardiac  function. 

Local  vasoconstrietion  in  different  parts  of  the  body  is  much  more 
common  than  general  vasoconstrietion.  The  cutaneous,  cerebral,  coro- 
nary, and  intestinal  vessels  are  especially  likely  to  be  thus  affected 
(Pal).  Spasmodic  persistent  contractions  of  the  renal  vessels  may 
also  occur  as  a  result  of  reflex  influences  (reflex  anuria) . 

Cold  causes  a  constriction  of  the  cutaneous  vessels  not  only  at  the 
place  of  application  but  reflexly  all  over  the  whole  surface  of  the  body. 
If  the  vasomotor  centres  be  very  excitable,  cold  may  thus  be  respon- 
sible for  disturbances  of  the  circulation.  In  a  similar  manner  the 
toxins  of  various  infections  cause  spasmodic  contraction  of  the 
cutaneous  vessels,  and  chills  result.  In  certain  forms  of  shock  the 
same  conditions  may  be  observed,  while  in  other  conditions  the  con- 
traction of  the  cutaneous  vessels  may  be  brought  about  secondarily,— 
for  example,  through  diminution  of  the  amount  of  blood  in  certain 
anaemias  or  as  a  result  of  its  concentration  in  the  algid  stage  of 
cholera. 

Cutaneous  vascular  cramp  causes  pallor  and  a  feeling  of  coldness. 
This  type  of  vasomotor  disturbance  is  especially  likely  to  occur  in 
the  extremities,  and  ranges  from  that  of  slightest  degree  causing  cold 
hands  and  feet  up  to  the  most  severe  type  such  as  occurs  in  Raynaud's 


TREATMENT  OF  VASOCONSTRICTION  325 

disease.  These  vascular  crises  in  the  internal  organs  cause  the  so-called 
vessel  pain  (Gefasschmerz)  and  attacks  of  functional  disturbance  in 
the  organs  whose  blood  supply  is  thus  rendered  intermittent  (intermit- 
tent claudication).  Such  would  appear  to  be  the  cause  of  stenocar- 
dial  attacks  or  angina  pectoris.  The  hypothetical  explanation  of  such 
disturbances,  as  resulting  from  vascular  cramp,  often  finds  its  best 
corroboration  in  the  curative  effect  of  vasodilating  drugs  or  agents. 
In  certain  forms  of  migraine  it  would  appear  that  chronic  contrac- 
tion of  the  meningeal  vessels  is  more  or  less  responsible  for  at  least 
a  part  of  the  trouble.  Other  varieties  of  headache — for  example,  that 
in  fever  and  in  urasmia — are  also  attributed  to  a  spastic  contraction  of 
the  cerebral  vessels.  It  may  be  that  sea-sickness  also  stands  in  some 
causal  relationship  to  such  tonic  contraction  of  these  vessels  [see  note, 
p.  325.— TR.]. 

Finally,  it  would  appear  that  in  different  conditions  of  stenocardia 
and  related  disorders  the  causal  moment  is  a  suddenly  occurring 
contraction  of  the  coronary  vessels  (B.  Breuer).  In  such  cases  the 
vascular  crises  may  occur  simultaneously  in  several  regions  and  may 
pass  from  one  to  another.  For  example,  in  angina  pectoris  the  tonic 
contraction  may  extend  from  the  cutaneous  vessel  of  the  upper  ex- 
tremities to  the  coronary  vessels. 

The  general  blood-pressure  is  affected  by  the  local  vascular  crises 
only  when  these  involve  extensive  vascular  systems,  as,  for  example, 
in  the  case  of  lead  colic,  where  the  intestinal  vessels  are  tonically 
contracted.  On  account  of  the  extent  of  the  cutaneous  vascular 
system  in  man,  vascular  crises  limited  to  the  vessels  of  this  system 
may  also  affect  the  aortic  blood-pressure.  However,  in  most  cases 
the  blood  forced  out  from  the  constricted  system  finds  a  place  in  other 
parts — for  example,  in  the  vessels  of  the  brain — which  dilate  when 
the  vessels  of  other  regions  are  tonically  contracted.  This  would 
appear  to  explain  the  frequently  observed  coincidental  occurrence  of 
Id  feet  and  hot  head. ' ' 

The  regional  vascular  crises  are  a  result  of  autochthonously  or 
exly  caused  excitation  of  the  appropriate  vasoconstrictor  centres, 
>ut  it  appears  that  changes  in  the  vessel  walls,  such  as  are  found  in 
arteriosclerosis  and  chronic  nicotine  poisoning,  dispose  to  their  occur- 
ce.  In  accordance  with  these  facts,  visceral  crises  may  be  relieved 
drugs  (narcotics)  diminishing  the  excitability  of  the  vasomotor 
;ntres,  and  also  by  those  acting  peripherally,  which  diminish  the 
pathologically  increased  tonus  of  the  vessel  walls  or  render  them  less 
susceptible  to  the  influence  of  the  vasomotor  centre.  Caffeine  and 
theobromine  are  examples  of  drugs  acting  in  the  latter  fashion,  while 
amyl  nitrite  and  the  other  nitrites,  with  their  central  and  peripheral 
vasodilating  action,  take  an  intermediate  position. 

The  narcotics  of  the  alcohol-chloroform  group  are  of  value  as 
vasodilating  drugs  in  so  far  as  they,  like  alcohol,  are  otherwise  not 
very  poisonous,  or,  like  chloral  hydrate,  even  in  small  doses  [  ?  — TR.]. 


326  PHARMACOLOGY  OF  CIRCULATION 

depress  the  vasomotor  centres.  They  act,  it  is  true,  on  the  vasomotor 
tone  of  all  the  vascular  systems,  but  certain  systems — above  all,  the 
cutaneous  and  the  cerebral  vessels — are  especially  readily  dilated  by 
them.  Still  more  elective  is  the  relaxing  effect  on  the  cutaneous 
vessels  exerted  by  the  members  of  the  antipyrine  group,  which  will  be 
further  discussed  in  the  section  on  the  pharmacology  of  temperature 
regulation.  These  drugs  are  especially  efficient  in  relieving  the 
tonic  contraction  of  the  cutaneous  vessels  which  occurs  in  chills. 
These  antipyretic  and  sedative  drugs,  moreover,  influence  the  circu- 
lation of  the  brain  in  even  smaller  doses.  As  shown  by  Wiechowski. 
antipyrine  and  related  drugs,  in  febrile  animals,  cause,  as  their  first 
appreciable  vasomotor  effect,  a  distinct  dilatation  of  the  intracranial 
vessels,  while  the  narcotics — for  example,  chloral  hydrate — increase 
the  flow  of  blood  through  the  brain  only  as  one  of  the  effects  of  a 
very  wide-spread  vasodilatation.  It  may  be  that  the  favorable  action 
of  chloral  hydrate  and  other  hypnotics  in  sea-sickness  *  rests  on  such 
a  dilatation  of  the  cranial  vessels  (Binz}. 

The  vasodilating  action  of  moderately  concentrated  alcohol 
(brandy  or  strong  wine)  produces  quick  and  useful  effects  when  the 
cutaneous  vessels  are  tonically  contracted, — as,  for  example,  in  chills 
or  in  the  faulty  reaction  which  results  from  a  persistent  contraction 
of  these  vessels  following  a  cold  bath.  Alcohol  may  also  prove  useful 
in  certain  cases  of  angina  pectoris  (Sahli). 

It  is  probable,  too,  that  the  favorable  effect  of  alcohol  in  certain 
conditions  of  collapse,  in  which  the  circulatory  failure  is  the  result 
of  faulty  heart  function,  is  to  be  explained  by  the  rapid  lessening  of 
the  tension  of  the  vessels  which  is  produced  by  proper  doses.  How- 
ever, it  should  be  remembered,  in  this  connection,  that  small  doses 
of  alcohol  dilate  the  cutaneous  vessels,  and  that,  according  to  more 
recent  experiments  (p.  274) ,  they  constrict  the  visceral  vessels.  It  may 
be,  however,  that  doses,  which  produce  no  effect  on  the  blood-pressure 
in  the  normal  circulation,  will  depress  the  tone  of  vessels  tonically 

contracted. 

BIBLIOGRAPHY 

Binz:  Zentralbl.  f.  inn.  Med.,  1903,  No.  9. 

Breuer,  R.:  Miinchn.  med.  Woch.,  1902,  No.  39. 

Miiller,  O.:  Deut.  med.  Woch.,  1906,  No.  39. 

Pal:  Die  Gefasskrisen,  Leipzig,  1905. 

Romberg:  21.  Kongr.  f.  inn.  Med.,  1904. 

Sahli:   19.  Kongr.  f.  inn.  Med.,  1901. 

Waller:  Ludwig's  Arb.  a.  d.  Physiol.  Anstalt  zu  Leipzig,  1878. 

Wiechowski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48,  p.  376. 

*  [It  would  appear  fairly  certainly  established  that  sea-sickness  is  the  result 
of  the  effect  produced  by  the  movements  in  space  of  the  labyrinth  of  the  ear,  and 
that  vasomotor  phenomena  are,  as  it  were,  simply  the  reflexly  produced  effects 
of  this.     If,  as  appears  to  be  the  case,  the  hypnotic  drugs  do  favorably  influence 
the  svmptoms  of  sea-sickness,  a  more  plausible  explanation  would  be  that 
do  so'  partly  by  interfering  with  the  reflexes  and  partly  by  lessening  the  unpleas 
ant  subjective  symptoms  of  this  condition,  for  both  of  these  effects  would  result 
from  their  general  depressing  influence  on  the  central  nervous  system. — TB.] 


TREATMENT  OF  VASCULAR  SPASM  327 

The  Nitrites. — Amyl  nitrite  and  similar  drugs  are  the  most  rapid 
and  powerful  vasodilating  agents  which,  we  possess.  They  are  the 
vasodilators  par  excellence.  As  may  be  shown  by  direct  observation, 
the  action  of  small  doses  is  electively  limited  to  dilatation  of  the 
cutaneous  vessels  of  the  upper  part  of  the  body  and  those  of  the 
brain,  while  in  larger  doses,  by  action  on  the  centres,  they  relax 
the  vessels  throughout  the  body  [with  the  exception  of  the  pulmonary 
vessels. — TR.]  In  addition,  they  also  act  locally  on  the  vessel  walls, 
as  shown  by  their  effect  on  the  coronary  vessels.  Lauder-Brunton 
introduced  amyl  nitrite  into  the  therapy  of  angina  pectoris  in  1867, 
and  in  practice  this  drug  has  shown  itself  extremely  effective  symp- 
tomatically  in  the  treatment  of  this  condition. 

As  is  well  known,  the  symptom-complex  of  angina  pectoris  occurs 
in  heart  disease  of  different  types,  and  consists  in  sudden  attacks1  of 
precordial  pain  associated  with  a  feeling  of  anxiety  and  depression, 
which  may  be  accompanied  by  more  or  less  marked  dyspnrea.     Pathol- 
ogists  believe  that  it  is  probably  caused  by  a  sudden  interference 
with  the  blood  supply  of  some  portion  of  the  heart,  for,  at  the  autopsy 
of  such  cases,  sclerosis  of  the  coronary  arteries,  causing  narrowing 
at  their  mouths  or  in  their  course1,  is.  often  found.     It  may,  there- 
fore, be  assumed  that  the  chief  cause  of  these  attacks  is  a  diminished 
blood  flow  in  the  coronary  arteries  or  their  faulty  power  of  accommo- 
dation to  the  need  of  an  increased  blood  supply,  to  the  heart  (Krehl). 
If  this  be  so,  it  is  easy  to  understand  the  successful  results  of  the 
administration  of  a  drug  possessing  such  exquisite  vasodilating  actions. 
The  most  probable  supposition  concerning  the  method  by  which 
this  effect  is  produced  would  be  that  amyl  nitrite  possesses  special 
owers  of  dilating  the  coronary  arteries  by  action  on  the  vasomotor 
entres  controlling  these  vessels.      Unfortunately,  our  knowledge  of 
eir  central  innervation  does  not  permit  us  to  state  that  the  drug 
erts  this  elective  action.     On  the  other  hand,  Loeb's  investigations 
ave  proved  that  amyl  nitrite  may  dilate  the  coronary  vessels  by  a 
>cal  action  on  their  walls. 

Furthermore,  the  vasodilatation  produced  by  amyl  nitrite  may 
iminish  the   demands  made  on  the  heart  in  case  constriction  of 
essels  in  other  regions  has  caused  a  relative  cardiac  insufficiency. 
Thus,  the  favorable  action  of  amyl  nitrite  in  angina  pectoris  may 
e  explained  quite  apart  from  any  direct  action  on  the  coronary 
irculation,  for  it  may  be  due  to  the  lessening  of  the  resistance  against 
hich  the  heart  must  work,  resulting  from  the  immediate  vasodilata- 
ion  which  follows  the   administration   of  this  drug.     In   cases   of 
nocardia  the  efficiency  of  other  vasodilatating  drugs — for  example, 
alcohol — may  be  explained  in  a  similar  fashion.      [As  it  has  been 
shown   by   McKenzie    and   others   that    angina   pectoris    frequently 
occurs  without  any  evidence  of  general  vasoconstriction  and  in  the 


328 


PHARMACOLOGY  OF  CIRCULATION 


presence  of  normal  blood-pressure,  it  does  not  appear  probable  that 
the  relief  which  it  so  often  gives  in  this  condition  is  a  result  of  its 
general  vasodilating  action. — TR.] 

Amyl  nitrite  does  not  always  entirely  or  even  partially  relieve 
the  attacks  of  angina  pectoris,  nor  should  this  be  expected,  for  it 
would  appear  that  this  symptom-complex  often  results  from  different 
causes.  Consequently,  success  should  be  expected  to  result  from  its 
administration  only  when  extensive  vasoconstriction  is  the  exciting 
cause.  [?  See  above. — TR.]  Its  efficiency  is  most  readily  understood 


a.  Tense  pulse  (angina  pest).     6.  After  amyl  nitrite. 


Tense  pulse  before  amyl  nitrite. 


After  five  drops  of  amyl  nitrite  (Pal). 
Fia.  36. 

in  those  forms  of  angina  described  by  Nothnagel  as  angina  pectoris 
vasomotoria,  in  which  "pallor  and  numbness,  subjective  feeling  of 
cold,  and  objective  decrease  in  temperature  of  the  skin"  would  indi- 
cate that  the  tonic  contractions  of  the  cutaneous  vessels  inaugurate 
the  attack. 

The  effects  of  the  inhalation  of  a  few  drops  of  amyl  nitrite  appear 
extremely  rapidly,  in  less  than  a  minute,  and  often  last  an  extremely 
short  time,  but  frequently  the  temporary  vasodilatation  produced  is 
able  to  correct  the  pathological  conditions  for  a  considerable  period. 
Lauder-Brunton  thus  describes  a  case  in  which  he  first  used  amyl 


TREATMENT  OF  VASOCONSTRICTION 


329 


nitrite.  ' '  Simultaneously  with  the  flushing  of  the  face  the  pain  disap- 
peared completely,  and  did  not  return  until  the  following  night. 
While  sometimes  the  pain  returned  after  about  five  minutes,  renewed 
inhalation  of  a  few  drops  caused  it  to  disappear  again,  and  this 
time  for  a  considerable  period."  At  the  same  time  with  the  relief 
of  the  attack,  the  cessation  of  the  tonic  contraction  of  the  vessels 
is  clearly  seen  in  the  radial  pulse.  This  is  graphically  shown  in 
sphygmograms  taken  by  Lwuder-Brunton. 

Amyl  nitrite  has  also  been  used  in  other  conditions  of  disease  in 
which  more  or  less  tonic  contraction  of  the  vessels — for  example,  of 
the  cerebral  vessels — has  been  assumed.  In  this  connection,  the  use 
of  amyl  nitrite  would  appear  rational  in  certain  types  of  migraine 
in  which  a  striking  pallor  of  the  face  indicates  vascular  constriction 
(hemicrania  sympathico-tonica) .  Quite  beyond  question  is  the  effect 
of  this  drug  on  the  tonic  contraction  of  the  splanchnic  vessels  when 
it  is  used  in  lead  colic,  the  abnormally  tense  and  retarded  pulse 
becoming,  at  least  temporarily,  quite  normal  (Fig.  37)  (Frank, 
Riegel) . 


(6) 


FIG.  37. — o,  pulse  during  lead  colic;  6,  after  amyl  nitrite. 

The  various  nitrites  act  analogously  to  amyl  nitrite,  but  in  general 
produce  more  lasting  effects.  After  sodium  nitrite  (in  doses  of  0.03- 
0.06  eg.)  the  effect  is  produced  in  3-4  minutes,  reaches  its  maximum  in 

0  minutes,  and  lasts  about  l1/^  hours  (Marshall,  M.  Hay). 
As  a  general  thing,  however,  the  action  of  sodium  nitrite  is  con- 
.dered  to  be  less  certain,  while  larger  doses — e.g.,  0:5  gm. — produce 
>xic  effects. 

The  nitric  acid  esters  of  the  higher  alcohols  also  possess  a  pro- 
>unced  nitrite  action.  Thus,  nitroglycerin,  in  the  very  small  amounts 
%— 1  mg.,  produces  in  two  minutes  the  same  actions  on  the  vessels 
the  nitrite  salts.  This  similarity  in  the  effects  of  the  nitric  acid 
esters  with  those  of  the  nitrites  is  due  to  the  fact  that  the  former  are 
changed  in  the  body  into  nitrites.  Nitroglycerin  possesses  the  advan- 
tage over  amyl  nitrite  in  that  its  effects  last  longer  (l%-3  hours) 
[see  above. — TR.].  The  same  is  true  of  erythrol  tetranitrate  and 
other  similar  compounds.  It  is  stated  that  sodium  nitrate  in  larger 
oses  acts  similarly  to  the  nitrites  (M.  Hay),  perhaps  because  in  the 
'dy  it  is  partially  reduced  to  a  nitrite. 


330  PHARMACOLOGY  OF  CIRCULATION 

BIBLIOGRAPHY 

Frank,  A.:  Arch.  f.  klin.  Med.,  1875,  vol.  16. 

Hay,  M.:   The  Practitioner,  1883. 

Krehl:  Die  Erkrankungen  d.  Herzmuskels,  in  Nothnagel's  Spez.  Path.  u.  Ther 

Wien,  1901,  p.  153. 

Lauder-Brunton :   Clin.  Soc.  Rep.,  London,  1870. 
Lauder-Brunton :  Deut.  med.  Woch.,  1902,  No.  16. 
Lauder-Brunton:   Lancet,  1867. 
Lauder-Brunton:  Pharmaceut.  Journ.,  1888. 
Loeb:   Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  51,  p.  64. 
Marshall:  A  Contribution  of  the  Pharmacol.  Action   of  the  Organic  Nitrates, 

Manchester,  1899. 
Nothnagel :  Ztschr.  f .  klin.  Med.,  1891,  vol.  19. 

Caffeine  and  theobromine  and  related  substances  dilate  the  vessels 
in  certain  regions  by  a  peripheral  action  on  the  vessel  walls.  On 
page  274  it  has  been  stated  that  caffeine,  by  its  action  on  the  vasomotor 
centres,  produces  an  opposite  (vasoconstricting)  effect,  which  affects 
especially  the  visceral  vessels  that  are  particularly  easily  influenced 
by  the  vasomotor  centres.  There  is  thus  an  antagonism  between 
its  central  vasoconstricting  action  and  its  direct  peripheral  vasodilat- 
ing  action,  in  one  group  of  vessels  the  peripheral  action  predominating, 
and  in  another  the  central.  As  long  as  the  kidney  remains  under  the 
influence  of  the  vasomotor  centres,  as  a  general  rule  its  vessels  will 
be  constricted  by  caffeine  [?TR.],  and  to  a  greater  or  less  extent 
according  to  the  varying  individual  susceptibility  of  the  vasomotor 
•centres  to  the  action  of  the  drug.  On  the  other  hand,  caffeine  always 
acts  as  a  vasodilator  in  a  kidney  isolated  from  its  nervous  connec- 
tions. With  theobromine,  which  has  less  action  on  the  centres,  the 
vasodilating  action  on  the  renal  vessels  always  preponderates.  (See 
section  on  diuresis.) 

Next  to  the  renal  vessels  the  cerebral  arteries  are  especially 
affected  by  the  peripheral  action  of  caffeine.  Wiechowski  observed, 
during  the  action  of  caffeine,  not  only  an  increased  flow  through 
the  brain,  which  he  explained  as  the  passive  result  of  the  forcing  out 
of  the  blood  from  the  splanchnic  system,  but  also  a  direct  depression 
of  the  tone  of  the  intercranial  vessels.  The  curative  action  of 
caffeine  in  certain  types  of  headache  may  be  due  to  this  action  on 
the  cranial  circulation. 

Finally,  experiments  of  Hedbom  and  Loeb  indicate  that  caffeine 
•distinctly  dilates  the  coronary  vessels  by  a  peripheral  action  on  the 
vessel  walls,  as  it  does  this  in  the  isolated  perfused  heart.  Theo- 
l)romine  acts  similarly,  and  this  is  probably  the  explanation  of  the 
fact  that  theobromine  preparations  have  proven  so  satisfactory  in 
the  prophylaxis  of  anginal  attacks  [and  in  other  vascular  crises.— 
TR.]  .  During  the  attacks,  however,  it  cannot  be  used,  as  its  absorption 
is  too  slow  to  relieve  promptly  the  tonic  contraction  of  the  vessels. 
The  prophylactic  employment  of  2.0-2.5  gm.  of  theobromine-sodium 
salicylate  prevents  or  moderates  these  attacks  in  unmistakable  fash- 


TREATMENT  OF  VASOCONSTRICTION  331 

ion,  as  has  been  evidenced  by  numerous  observations  made  since  it  was 
first  recommended  for  this  purpose  by  Askanazy.  Theobromine  and 
the  closely  related  theocin  have  also  been  found  useful  in  the  prophy- 
laxis of  other  conditions  dependent  on  vascular  crises.  This  is  prob- 
ably due  to  the  fact  that  the  depression  of  the  peripheral  tonus  of  the 
vessels  resulting  from  the  action  of  these  drugs  renders  them  less 
susceptible  to  the  occasionally  recurring  excitation  of  the  vasomotor 
centres  (Breuer). 

The  alkaloid  yohimbin  (p.  289)  also  dilates  certain  vascular  systems 
by  a  peripheral  action.  Its  nitrate,  vasotonin,  in  probably  superfluous 
combination  with  very  small  amounts  of  urethane,  has  been  recently 
recommended  for  subcutaneous  injection  in  the  treatment  of  angina 
pectoris  or  other  arteriosclerotic  disturbances  (Muller  u.  Fellner, 
Staeheliri) . 

BIBLIOGRAPHY 

Askanazy:    Deut.  Arch.  f.  klin.  Med.,  1895;  Deut.  Zentralbl.  f.  klin.  Med.,  1895. 

Breuer,  R.:   Miinchn.  med.  Woch.,  1902,  Nos.  39-41. 

Hedbom:   Skand.  Arch.  f.  Physiol.,  1899,  vol.  9,  p.  1. 

Loeb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  51,  p.  64. 

Muller,  Fr.,  u.  Fellner:  Therap.  Monatshefte,  1910,  June. 

Staehelin:     Therap.  Monatshefte,   1910,  September. 

Wiechowski :    Arch,  f .  exp.  Path.  u.  Pharm.,  1902,  vol.  48,  p.  376. 


CHAPTER  IX 


THE  respiratory  system  of  mammals  consists  in  the  integral  por- 
tions of  the  respiratory  tract,  the  larynx,  bronchi,  and  lungs,  and  in 
the  muscles  which  control  them,  these  being,  in  part,  the  striated 
laryngeal,  intercostal,  and  diaphragmatic  muscles  and  the  unstriped 
muscles  of  the  bronchi.  The  respiratory  exchange  of  gases  in  the 
pulmonary  alveoli  depends  on  the  atmospheric  pressure,  the  activity 
of  the  motor  mechanism  of  the  respiratory  muscles,  and  the  elasticity 
of  the  pulmonary  tissues, — i.e.,  on  the  mechanical  effects  of  the 
respiratory  movements,  as  well  as  on  the  resistance  which  opposes 
the  movement  of  the  air  in  the  air-passages,  and  the  elastic  contraction 
and  relaxation  of  the  alveoli. 

The  frequency,  extent,  and  power  of  the  movements  of  respiration 
are  directly  dependent  on  the  state  of  excitation  of  the  respiratory 
centres,  situated  in  the  medulla  and  spinal  cord,  which  are  stimulated 
directly  by  substances  present  in  the  blood  and  reflexly  through  cen- 
tripetal nerves,  especially  the  pulmonary  vagus,  the  trigeminus, 
and  the  cutaneous  nerves. 

Of  the  factors  which  influence  the  excitation  of  the  respiratory 
centre  through  the  blood,  oxygen  and  carbon  dioxide  tension  are 
the  decisive  ones.  Abnormally  diminished  02  tension  in  the  blood 
increases  the  frequency  and  depth  of  the  respiration,  causing,  as  a 
rule,  a  dyspncea  of  a  predominatingly  inspiratory  type,  but  this 
occurs  only  when  the  O2  content  of  the  inspired  air  has  sunk  to  10 
per  cent,  or  less  (Speck,  Loewy,  v.  Terray).  If  at  the  same  time 
the  tension  of  C02  is  very  low,  lack  of  02  causes  Cheyne-Stokes  res- 
piration (Haldane  and  Douglas).  This  is  the  explanation  of  the 
appearance  of  this  phenomenon  in  high  altitudes  (Durig}. 

OXYGEN  INHALATIONS. — No  appreciable  effect  on  the  respiratory 
apparatus  or  on  the  consumption  of  O2  and  the  total  metabolism 
results  from  an  increase  of  the  02  contents  of  the  air  respired,  even 
when  this  amounts  to  100  per  cent.  (Durig,  Kraus).  Except  in  CO 
poisoning  there  is  no  sufficient  scientific  proof  of  the  value  of  inhala- 
tions of  O2,  although  these  have  recently  been  strongly  recommended 
by  clinicians  (McKenzie  et  al.}. 

Most  observers,  however,  report  that  the  inhalation  of  O2  exerts  a 
favorable  effect  on  the  subjective  feelings  of  patients  suffering  with 
dyspnoea  and  cyanosis, — at  any  rate,  as  long  as  the  inhalation  is 
continued.  Inasmuch  as  haemoglobin  cannot  absorb  more  oxygen  from 
a  gas  mixture  rich  in  O2  than  from  the  air,  this  effect  cannot  be 
attributed  to  a  greater  saturation  of  the  blood-coloring  matter  with 
332 


DIRECT  RESPIRATORY  STIMULANTS  333 

oxygen.  However,  the  plasma  can  absorb  more  oxygen  if  the  oxygen 
tension  of  the  inspired  air  is  higher  than  in  the  ordinary  air,  and 
thus  it  may  at  times  be  of  some  importance  to  increase  the  oxygen 
tension  in  the  inspired  air  (Durig),  for  plasma  saturated  with  oxygen 
to  an  abnormally  high  degree  may  raise  to  the  normal  the  oxygen 
tension  in  blood  which  is  unequally,  and  therefore  incompletely,  arte- 
rialized  on  account  of  the  existence,  here  and  there  in  the  lungs,  of 
pathological  conditions  interfering  with  the  gaseous  interchange  be- 
tween the  blood  and  the  air.  It  may  be  that,  as  a  result,  the  metabolic 
products  which  cause  dyspnoea  are  more  rapidly  oxidized,  and  that 
thus  the  restlessness  and  the  feeling  of  anxiety  due  to  the  dyspnoea 
may  be  relieved. 

If,  as  a  result  of  persistent  over-saturation  of  the  blood  with  CO2 
in  pulmonary  stasis  of  cardiac  origin,  or  as  a  result  of  ursemic  poison- 
ing, the  respiratory  centre  has  been  blunted  to  the  stimulation  pro- 
duced by  C02,  an  insufficient  oxygen  supply  frequently,  in  spite  of 
high  C02  tension  of  the  blood,  causes  a  condition  to  develop  which  is 
characterized  by  periodic  breathing,  the  patient  falling  asleep  during 
the  pauses  and  waking  suddenly  and  anxiously  when  the  respirations 
start  again.  In  such  conditions  inhalation  of  02  can  often  bring  about 
regular  breathing  once  more  and  thus  give  marked  relief  (personal 
communication,  B.  Breuer) .  From  the  above,  the  symptomatic  effects 
of  the  inhalation  of  02,  especially  those  obtained  as  long  as  the  inhala- 
tion continues,  may  be  explained  (see  also  Loewy  and  Zuntz). 

EFFECTS  OF  THE  CARBON  DIOXIDE  TENSION  OF  THE  BLOOD. — On 
the  other  hand,  a  diminution  of  the  normal  C02  tension  in  the  alveoli, 
and  consequently  also  in  the  tissues,  has  no  stimulating  effect  on  the 
respiration,  while  an  increase  of  the  C02  tension,  even  a  very  slight 
one,  markedly  stimulates  respiration  (Jacquet).  Increased  C02  ten- 
sion in  the  tissues  also  occurs  if  the  alkalinity  of  the  blood  be  dimin- 
ished, a  condition  which  may  result  from  the  formation  of  acid 
metabolic  products  during  hard  muscular  work  or  in  fever,  diabetes, 
many  poisonings,  etc.  (Geppert  and  Zuntz).  In  such  case  the  res- 
piration becomes  very  dyspnoeic.  It  is  enlightening  that  under  such 
conditions  the  free  administration  of  alkalies  may  quiet  and  regulate 
the  respiration. 

EFFECTS  OF  BODY  TEMPERATURE. — Without  regard  to  its  chemical 

position,  the  temperature  of  the  blood  also  exerts  an  influence  on 
the  frequency  and  depth  of  respiration,  increased  temperature  usually 
stimulating  (Pick  u.  Goldstein,  v.  Mertschinsky,  Fridericq,  R.  H. 
Eahn)  and  lowered  temperature  depressing  it.  Therefore,  all  agents 
which  warm  abnormally  cooled  blood — for  example,  warm  perfusions 
— or  which,  like  the  antipyretics,  cool  the  overheated  blood  of  fever 
will  aid  in  bringing  the  frequency  of  the  respirations  back  toward 
.e  normal. 


334  PHARMACOLOGY  OF  THE  RESPIRATION 


BIBLIOGRAPHY 

Durig:  Wien.  akad.  Denkschr.,  1910,  vol.  86,  p.  374. 

Durig:   Engelmann's  Arch.,  1903,  Suppl.,  p.  209. 

Fick  u.  Goldstein:  Wiirzburg.  Verb.,  1871,  No.  7. 

Tick  u.  Goldstein:  Pfluger's  Arch.,  1872,  vol.  5,  p.  38. 

Fridericq:  Dubois'  Arch.,  Suppl.,  1883,  p.  51. 

Geppert  u.  Zuntz:  Pfluger's  Arch.,  1888,  vol.  42,  p.  189. 

Haldane  and  Douglas:  Journ.  of  Physiol.,  1910,  vol.  38,  p.  401. 

Jaquet:   Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30. 

Kahn,  E,.  H.:  Engelmann's  Arch.,  1904,  Suppl.,  p.  81. 

Kraus :   Ztschr.  f .  klin.  Med.,  1893,  vol.  22,  p.  449. 

Loe,wy:   Pfliiger's  Arch.,  1894,  vol.  58,  p.  409. 

Loewy:    Unters.  tiber  d.  Resp.  u.  Cir.  bei  And.  d.  Druckes  u.  d.  Sauerstoffgehalts 

d.  Luft,  Berlin,  1895. 

Loewy  u.  Zuntz:  in  Michaelis,  Sauerstofftherapie,  Berlin,  1905. 
McKenzie,  James:    Diseases  of  the  Heart, 
v.  Mertschinsky :   Wiirzb.  Verh..  vol.  16,  1881. 
Speck:   Physiol.  d.  menschl.  Atmens,  Leipzig,   1892. 
v.  Terray:  Pfluger's  Arch.,  1897,  vol.  65,  p.  383,  here  literature. 

DIRECT  OR  CENTRAL  RESPIRATORY  STIMULANTS 

In  cases  of  severe  illness  or  poisoning,  deep  coma  not  infrequently 
develops,  the  breathing  becoming  progressively  slower  and  shallower 
and  finally  entirely  insufficient.  In  such  case  the  therapeutic  indica- 
tion is  to  stimulate  the  respiration, — i.e.,  to  excite  the  halting  mechan- 
ism to  sufficient  activity.  This  can  be  accomplished  by  direct  stimu- 
lation of  the  respiratory  centre. 

The  number  of  substances  which  directly  stimulate  this  centre  is 
very  large.  It  may  be  stated  that  all  very  volatile  poisons  stimulate 
the  respiration,  and  inasmuch  as  these  substances  are  excreted  in  the 
expired  air,  this  stimulation  of  the  respiration  is  a  reaction  of  the 
organism  readily  understood  from  the  teleologic  point  of  view.  Hy- 
drogen sulphide,  HCN,  C02,  chloroform,  ether,  alcohol,  amyl  nitrite, 
and  many  others,  all  act  in  this  fashion,  but,  for  therapeutic  purposes, 
only  alcohol  and  ether  are  of  practical  importance  in  this  connection. 

ALCOHOL. — The  stimulating  effect  on  the  respiration  exerted  by 
small  amounts  of  strong  wines  has  long  been  known  clinically;  but 
the  question,  as  to  the  extent  to  which  this  is  a  reflex  effect  from 
the  stimulation  of  the  taste  and  smell  or  of  the  sensory  nerves  of  the 
stomach,  or  the  result  of  direct  stimulation  of  the  respiratory  cen- 
tres, has  been  responsible  for  numerous  investigations,  especially  on 
the  part  of  Binz  and  his  pupils. 

These  authors  have  been  able,  in  animal  experiments,  to  show  that  a 
persistent  increase  of  the  ventilation  volume — i.e.,  of  the  volume  of  air 
breathed  in  and  out  in  the  unit  of  time — resulted  from  the  administra- 
tion of  alcohol  irrespective  of  the  manner  in  which  it  was  administered. 
This  occurred  even  after  intravenous  injection,  while,  when  the  alco- 
hol was  injected  toward  the  centre  into  the  carotid  artery,  the  effect 
was  produced  almost  instantaneously  (Wilmanns).  From  this  last- 


DIRECT  RESPIRATORY  STIMULANTS  33S 

mentioned  observation  it  is  permissible  to  deduce  a  direct  stimulating- 
action  in  the  central  nervous  system.  Moreover,  as  alcohol,  unlike 
carbohydrates  and  fats,  cannot  be  stored  up,  but  is  promptly  com- 
busted, a  part  of  the  persistently  increased  respiration  must  be  attrib- 
uted to  the  larger  demand  for  02  and  the  greater  production  of  C02 
resulting  from  the  combustion  of  the  alcohol  (Henri jean,  Zuntz} .  As,, 
however,  this  action  occurs  even  after  the  intravenous  administration 
of  very  small  doses,  whose  combustion  can  hardly  produce  such  effects, 
the  chief  cause  of  the  increased  respiration  must  be  sought  in  a  direct 
central  stimulation.  According  to  Binz,  the  ethers  present  in  wines, 
also  possess  the  property  of  stimulating  the  respiratory  centres. 

ETHEB  may  be  administered  internally  either  pure  or  mixed  with 
alcohol  in  Hoffmann's  anodyne.  Subcutaneous  injections  of  ether  are 
also  very  efficient,  but  they  must  not  be  administered  in  the  neigh- 
borhood of  nerve-trunks.  [Administered  in  these  varying  fashions 
this  drug  strongly  stimulates  the  respiration  partly  reflexly  and  partly 
directly.— TR.] 

In  addition  to  the  above-mentioned  volatile  substances,  the  respira- 
tory centre  is  stimulated  by  a  number  of  drugs  which  increase  the 
excitability  of  different  portions  of  the  central  nervous  system.  In 
this  connection,  particular  mention  should  be  made  of  strychnine, 
camphor,  caffeine,  cocaine,  atropine,  and  other  alkaloids  of  this  group^ 
lobeline,  apomorphine*  and  the  two  alkaloids  contained  in  quebracho 
bark,  aspidospermine  and  quebrachine  (B.  Wallace}.  For  practical 
purposes,  only  camphor,  caffeine,  and  atropine  need  be  considered. 
[Strychnine  ! — TR.] 

The  stimulating  action  of  camphor  and  the  methods  of  its  adminis- 
tration have  already  been  discussed,  as  also  that  of  caffeine.  In  this 
connection  it  may  be  mentioned  that  other  substances,  which  may  be 
obtained  by  distillation  and  which  increase  the  frequency  of  respira- 
tion, are  contained  in  tea  and  coffee  (Heinz,  Archangelsky) . 

BIBLIOGRAPHY 

Archangelsky :  Arch,  intern,  de  Pharmacodynamie,  1900,  vol.  7,  p.  405. 

Harnack:  Arch.  f.  exp.  Path.  u.  Pharm.,  1873,  vol.  2,  p.  254. 

Heinz:  Inaug.-Diss.,  Bonn,  1890. 

Henrijean:   Bull,  de  1'acad.  r.  de  Bruxelles  (3),  1883,  vol.  5,  No.  1. 

Krautwig,  P.:   Zentralbl.  f.  klin.  Med.,  1893,  No.  17. 

Wallace,  B.:   Proc.  Soc.  f.  Exp.  Biol.  and  Med.,  New  York,  1903-4,  vol.  1. 

Wendelstadt:   Pfliiger's  Arch.,  1899,  vol.  76,  p.  223,  lit.  here. 

Wilmanns:   Pfliiger's  Arch.,  1897,  vol.  66,  p.  167. 

Zuntz:  Verh.  d.  Berl.  phys.  Ges.,  Dubois'  Arch.,  1887,  p.  178. 

ATROPINE. — The  central  stimulation  of  respiration  by  atropine 
was  demonstrated  long  ago  by  Bezold  and  has  been  confirmed  by 

*  Apomorphine  stimulates  the  respiratory  centres  even  after  the  vomiting 
centres  have  been  paralyzed  in  narcosis  ( Harnack ) .  [It  later  depresses  them. — TB.) 


336 


PHARMACOLOGY  OF  THE  RESPIRATION 


various  other  observers.  It  is  especially  usefully  and  clearly  devel- 
oped in  narcotic  poisonings, — for  example,  in  chloral  poisoning  (Huse- 
mann)  and  particularly  in  morphine  poisoning.  The  following  curve 
(Fig.  38),  reproduced  from  Vollmer,  shows  graphically  the  results 
obtained  in  an  investigation  of  the  antagonistic  action  of  morphine  and 
atropine  on  the  respiration. 

As  large  toxic  doses  of  atropine  may  themselves  depress  the  respira- 
tory centres,  the  desired  success  depends  evidently  on  the  skilful  and 
careful  use  of  atropine,  and  this  depressing  action  explains  the  failures 
observed  in  the  experiments  of  various  investigators  (Binz). 


Gradua 
the  res 


0.06  mor 
iminuti 
iratory  v( 


Id 


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900O 


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700O 


6000 


SOW 


WOO 


3000 


Time   S.tO 


Fia.  38. 


INDIRECT  REFLEX  STIMULATION  OF  THE  RESPIRATORY  CENTRE  usually 
produces  more  marked  effect  on  the  respiration  than  that  caused  by 
the  use  of  drugs.  Such  reflex  stimulation  may  be  induced  by  cuta- 
neous irritation  (seep.  341)  and  by  irritation  of  the  nerve-endings 
of  the  trigeminal  and  olfactory  nerve  in  the  nose,  induced  mechani- 
cally, as  by  tickling,  or  chemically,  as  by  ammonia  or  vinegar.  The 
widely  used  smelling  salts  contain  ammonium  carbonate  with  ethereal 
oils,  such  as  the  oil  of  lavender. 


BIBLIOGRAPHY 

Bezold  u.  Blobaum:    Wiirzb.  physiol.  Untersuchungen,  1867,  vol.  1,  p.  1. 
Binz:   Berl.  klin.  Woch.,  1896,  p.  885. 

Husemann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1877,  vol.  6,  p.  443. 
Vollmer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30,  p.  385. 


RESPIRATORY  SEDATIVES 


337 


RESPIRATORY   SEDATIVES 

The  clinical  indication  is  much  oftener  that  of  quieting  and 
regulating  the  respiration  than  that  for  stimulation.  This  is  the  case 
where  a  directly  or  reflexly  induced  dyspnrea,  spasmodic  respiratory 
movements,  or  distressing  cough  demand  relief,  in  which  conditions 
symptomatic  relief  may  be  obtained  by  dulling  the  sensibility  of  the 
respiratory  centres. 

This  property  of  diminishing  the  excitability  of  the  respiratory 
centres  is  possessed  by  all  so-called  narcotics, — i.e.,  by  all  substances 
which  depress  the  excitability  of  the  central  nervous  system, — but 
the  various  narcotics  exhibit  marked  and  important  differences  in  this 
respect.  Although  all  the  anaesthetics  and  hypnotics,  belonging  to 
the  large  "alcohol  group,"  have  a  sedative  action  on  the  respiration, 
this  effect  results  only  from  more  or  less  toxic  doses,  which  appreciably 


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very  decidedly  blunt  the  consciousness,  the  sensibility,  and  the 
&Hex  excitability.  They  are  consequently  not  suitable  drugs  for  this 
indication.  [The  translator  most  emphatically  disagrees  with  this 
sweeping  statement,  for  he  believes  that  clinically  such  drugs  as 
chloral  and  other  commonly  used  hypnotics  may  frequently  be  em- 
ployed with  advantage  for  this  indication  and  in  doses  which  produce 
only  moderate  hypnotic  effects.] 

MORPHINE 

On  the  other  hand,  the  narcotics  of  the  morphine  group  depress 
the  excitability  of  the  respiratory  centre  in  a  very  specific  fashion, 
long  before,  or  without  at  all,  producing  other  sedative  effects. 

A.  Loewy  has  introduced,  as  a  very  useful  means  of  measuring  the  excita- 
bility of  the  respiratory  centre,  the  readily  graded  stimulation  which  results 
from  mixing  different  percentages  of  CO2  with  the  inspired  air.  In  man  the 
expired  air  contains  about  3  per  cent,  of  CO2.  If  the  inspired  air  be  mixed  with 
22 


338 


PHARMACOLOGY  OF  THE  RESPIRATION 


increased  quantities  of  CO2,  the  CO2  content  of  the  expired  air  rises  accordingly 
and  may  serve  as  a  measure  of  the  effective  CO2  tension  in  the  blood.  It  has 
been  shown  also  that  as  the  percentage  of  CO2  in  the  expired  air  rises  from  3  per 
cent,  to  about  7  per  cent,  the  respiratory  volume  increases  almost  exactly  pro- 
portionately, and  in  the  same  proportion  in  different  individuals  and  at  different 
times.  The  curves  in  Fig.  39,  reproduced  from  Loewy,  show  this  clearly. 
Apparently  with  higher  CO2  tension  a  summation  effect  from  different  unknown 
factors  develops,  for  the  ventilation  volume  increases  to  a  greater  extent  than 
corresponds  to  the  increase  of  CO2  in  the  expired  air. 

Neither  natural  sleep  nor  that  induced  by  hypnotics,  such  as 
chloral  hydrate,  chloralamide,  amylene  hydrate,  markedly  influences 
the  reaction  curve,  but  this  is  decidedly  altered  by  morphine,  even 
in  small  doses  which  otherwise  produce  no  sedative  effects.  Under 
its  influence  the  respiratory  centre  becomes  less  excitable,  so  that  the 
C02  in  the  inspired  air  must  be  increased  much  more  than  under 
normal  conditions  in  order  to  cause  the  usual  increase  in  respiration. 
The  sensibility  of  the  respiratory  centre  to  reflex  stimulation — such, 
for  example,  as  that  resulting  from  stimulation  of  the  sciatic — is  dimin- 
ished in  the  same  fashion  as  its  sensibility  to  C02. 

In  man,  after  very  small  doses  of  morphine  (3-10  mg.)  the  dimin- 
ished excitability  of  the  respiratory  centre  expresses  itself  by  slowed 
and  deepened  breathing,  for  a  stronger  summation  of  the  stimuli 
(distention  of  the  lungs  and  the  C02  tension  in  the  blood)  is  needed 
to  excite  the  rhythmic  respiratory  movements.  This  has  been  proven 
experimentally,  by  A.  Frankel,  who  observed  that  the  respirations  of 
rabbits  under  the  influence  of  morphine  occurred  less  frequently 
but  were  much  deeper. 

Effects  of  Small  Doses  of  Morphine  on  the  Respiratory  Volume 
of  the  Rabbit* 


Time, 
minutes 

No.  of  respira- 
tions per  min. 

C.c.  of  air  re- 
spired per  min. 

C.c.  of  air  in 
each  respiration 

1 

68 

300 

4.4 

2 

64 

300 

4.6 

3 

68 

300 

4.7 

5 

13 

54 

300 

5.7 

26 

60 

400 

6.6 

51 

52 

360 

6.9 

61 

50 

440 

8.8 

71 

56 

500 

8.9 

*  0.54  mg.  morphine  per  kilo  injected  subcutaneously. 

Under  certain  conditions,  morphine  may  thus  increase  the  ventila- 
tion in  the  lungs  beyond  the  normal,  for  during  each  respiration  only 
a  portion  of  the  alveolar  air  can  be  replaced  by  atmospheric  air,  and 
this  portion,  on  account  of  the  volume  of  air  contained  in  the  so-called 
"noxious  air-space"  of  the  trachea  and  bronchi,  must  be  considerably 
increased  by  a  deep  respiration  as  compared  to  the  amount  replaced 


RESPIRATORY  SEDATIVES  339 

during  a  shallow  one.  Thus,  for  example,  in  the  experiments  of 
Beach  and  Roder  (see  also  Loewy)  the  alveolar  air  was  found  to  con- 
tain 17  per  cent,  of  O2  and  2.7  per  cent,  of  carbonic  acid  when 
20  litres  of  air  were  respired  as  a  result  of  100  respirations  to  the 
minute.  When  the  respirations  were  deeper  and  slower,  the  same 
"minute  volume"  was  respired  with  only  25  respirations  to  the  minute 
and  the  02  in  the  alveolar  air  was  found  to  be  present  in  the  propor- 
tions of  19.3  per  cent,  and  carbonic  acid  in  that  of  2  per  cent.  In 
these  figures  the  greater  ventilating  effect  of  deep  and  slow  breathing 
is  clearly  apparent. 

This  effect  is  increased  by  the  fact  that  the  composition  of  the 
air  in  all  parts  of  the  lungs  is  not  the  same,  for  the  air  is  richest  in 
C02  and  poorest  in  O2  in  the  alveoli  lying  at  the  periphery,  which 
expel  their  contents  only  during  deep  breathing  and  more  especially 
during  forced  expiration.  For  this  reason  forced  expirations,  such  as 
occur  in  coughing  but  especially  during  sneezing  and  vomiting,  may 
exert  a  favorable  influence  on  the  renewal  of  air  in  the  alveoli. 
Herein  may  lie  a  partial  explanation  of  the  benefit  of  the  nausea  and 
the  retching  movements,  which  the  so-called  nauseating  expectorants 
induce  (Dreser). 

From  such  slowed  and  deepened  and,  in  spite  thereof,  more  effi- 
cient respirations,  the  lungs  and  the  whole  respiratory  system  may 
experience  a  beneficial  relief,  and  there  may  result  a  saving  of  strength 
which  may  be  of  greatest  importance  in  enfeebled  patients,  who  have 
been  breathing  frequently  and  ineffectively, — as,  for  example,  cardiac 
cases  or  cases  with  high  fever.  By  regulating  and  improving  its 
efficiency,  morphine  does  about  the  same  for  the  respiration  as  digitalis 
does  for  a  diseased  and  insufficient  heart. 

Effects  on  Cough. — The  reflex  excitability  of  the  cough  centre, 
which  is  reflexly  stimulated  by  irritation  of  the  laryngeal  and  bron- 
chial mucous  membranes  and  perhaps  also  by  reflexes  from  other 
organs,  is  depressed  by  drugs  of  the  morphine  group  even  earlier 
and  more  readily  than  is  that  of  the  respiratory  centre  proper.  This 
fact  has  been  established  clinically  beyond  all  doubt,  although  experi- 
mental proof  of  it  is  still  lacking,  and  consequently  drugs  of  the  mor- 
phine group  may  be  used  with  good  effect  in  conditions  where  the 
indication  is  to  suppress  the  cough  reflex,  as  in  harassing  or  painful 
cough,  or  with  the  idea  of  avoiding  haemoptysis,  or  to  relieve  laryngeal 
inflammation  or  irritation,  which  is  constantly  aggravated  by 
coughing. 

Morphine  Derivatives. — Although  these  therapeutic  effects  may  be 
obtained  by  the  use  of  morphine  in  proper  doses  (3-10  mg.  for  adults, 
correspondingly  smaller  doses  for  children),  still  its  other  effects,  such 
as  constipation  or,  in  nervously  susceptible  patients,  excitement,  as 
well  as  the  danger  of  opening  the  door  to  the  readily  acquired  habit  in 
chronic  sufferers,  such  as  tubercular  patients,  are  ample  reasons  for 


340  PHARMACOLOGY  OF  THE  RESPIRATION 

avoiding  as  long  as  possible  the  use  of  this  drug  for  the  relief  of 
cough.  This  is  the  more  feasible  as  certain  derivatives  of  morphine 
do  not  possess  the  disadvantages  mentioned  [in  the  same  degree. — TR.], 
while  they  produce  the  desirable  effects  on  the  respiratory  function 
in  even  higher  degree  (Heinz,  Dreser,  Frankel}.  Of  these  derivatives 
the  following  are  of  practical  importance: 

1.  CODEINE,  a  methylmorphine,  best  administered  as  codeine  phos- 
phate, which  is  readily  soluble  in  water.    It  may  be  used  several  times 
daily  in  doses  of  0.04-0.06  gm.  for  adults   (0.1  gm.  maximal  single 
dose,  0.3  gm.  maximal  daily  dose).     Smaller  doses,  even  when  fre- 
quently repeated,  are  of  slight  efficiency  and  are  not  to  be  recom- 
mended  (Frdnkel).     Habituation  need  not  be  feared,  even  in  case 
of  use  for  months  or  years. 

2.  DIONIN,  ethylmorphine  hydrochloride,   in  its  actions,   is  very 
similar  to  codeine,  but  it  appears  to  be  more  powerfully  analgesic  and 
constipating,    although   neither   of   these    actions    is    as   pronounced 
as  with  morphine.    It  may  be  administered  orally  or  subcutaneously  in 
doses  of  0.015-0.03  gm. 

3.  PERONIN,   benzoylmorphine   hydrochloride,    0.02-0.04   gm.   per 
dose.     [Is  little  used.    Resembles  dionin. — TR.] 

4.  HEROIN,  diacetylmorphine  hydrochloride,  which  is  readily  soluble 
in  water,  diminishes  the  excitability  of  the  respiratory  centre  more 
strongly  than  the  other  morphine  derivatives,  and  even  in  small  doses 
slows  and  deepens  the  respiration.    It  is  in  general  more  like  morphine 
than  the  other  derivatives  mentioned,  and  in  children  produces  a 
strong  narcotic  effect  (see  p.  38).    For  adults  the  dose.is  3-5  mg.,  for 
children  over  one  year  y2  mg->  under  one  year  %  mg.    With  this  drug 
there  is  danger  of  habit  formation. 

Still  other  substances  exert  a  sedative  action  on  the  respiratory 
centre,  as,  for  example,  camphoric  acid,  an  otherwise  but  slightly 
active  oxidation  product  of  camphor.  Dose,  1.0-2.0  gm.  It  may  be 
administered  in  alcoholic  solution  (Heinz  and  Manasse}. 

BIBLIOGRAPHY 

Dreser:  Verh.  d.  Ges.  d.  Naturfr.  u.  Aerzte,  Aachen,  1900,  vol.  2,  p.  26. 
Dreser:   Pfliiger's  Arch.,  1898,  vol.  72. 
Frankel,  A.:    Miinchn.  med.  Woch.,  1899,  No.  46. 
Frankel:  Miinchn.  med.  Woch.,  1899,  No.  24. 
Heinz:    Diss.,  Bonn.,  1890. 

Heinz  u.  Manasse:    Deut.  med.  Woch.,  1897,  No.  41. 
Loewy,  A.:   Pfliiger's  Arch.,  1890,  vol.  47,  p.  601. 
Loewy:   Respiration  u.  Circ.,  Berlin,  1895. 
Loewy:   Pfliiger's  Arch.,  1894,  vol.  58,  p.  416. 
Reach  u.  Roder:   Biochem.  Ztschr.,  1909,  vol.  22,  p.  471. 

EMBARRASSMENT  OF  THE  RESPIRATION 

Excluding  such  conditions  as  compression  of  the  lungs  by  air  or 

fluid  in  the  pleura!  cavity  and  those  where  the  respiratory  muscle 

is  mechanically  incapacitated, — for  example,  spasm  or  paralysis  of 

the  diaphragm, — inefficient  breathing  may  be  due  to  a  reflex  inhibition 


EMBARRASSMENT  OF  THE  RESPIRATION  341 

of  the  thoracic  movements  by  pleuritic  pain,  intercostal  neuralgia,  etc., 
to  an  abnormal  condition  of  the  air-passages,  or,  finally,  to  a  disturb- 
ance of  the  pulmonary  circulation.  Only  these  last  three  causes  may 
be  affected  by  medicinal  treatment. 

1.  Pain  may  interfere  with  the  movements  of  the  thorax  on  one 
or  both  sides.     This  may  be  experimentally  demonstrated  in  animals 
or  in  man  by  applying  mild  irritants,  such  as  mustard  plasters  or 
tincture  of  iodine,  to  one  or  both  sides.    The  precordial  region  appears 
to  be  by  far  the  most  susceptible  portion  of  the  thorax,  and  particu- 
larly so  to  irritation  by  mustard  plasters  (L.  Mayer).     As  a  result 
of  such  irritation  the  breathing  becomes  shallower  and  slower,  espe- 
cially in  its  inspiratory  portion,  while  the  unirritated  side  compen- 
sates with  increased  movement.     Such  irritation  of  the  healthy  side 
may  be  occasionally  carried  out  for  therapeutic  purposes  in  order  to 
bring  about  freer  movement  of  a  lung  which  has  become  more  or  less 
inactive   as   a   result    of   pleuritic   adhesions   or   other   pathological 
processes. 

If  the  counterirritation  be  very  powerful, — as,  for  example,  that 
caused  by  the  thermocautery, — the  movements  of  the  side  where  the 
irritation  is  applied,  although  becoming  slower,  do  not  become  less 
extensive,  but,  on  the  contrary,  marked  deepening  of  inspiration 
occurs,  which  may  last  for  some  time  after  the  active  irritation  has 
ceased.  Similar  favorable  effects  of  slowing  and  deepening  of  the 
respiration  may  result  from  milder  counterirritation — by  tincture  of 
iodine — in  case  the  breathing  has  been  shallow  and  rapid  as  a  result 
of  spontaneous  pain,  such  as  that  occurring  in  pleurodynia,  for  such 
mild  irritations  have  some  local  anaesthetic  action.  By  such  means  the 
respirations  of  the  patient  may  be  relieved  and  improved  (see  p.  34). 

In  inflammatory  conditions  of  the  mucous  membrane  of  the 
respiratory  tract,  drinking  or  gargling  with  emollients,  such  as 
althea  or  mucilage  of  acacia,  may  give  relief  by  their  effects  on  irritant 
reflexes. 

2.  Impairment  of  the  respiration  as  a  result  of  obstructions  in  the 
respiratory  tract  may  occur  as  a  result  of  an  inflammation,  on  account 
of  excessive  viscid  bronchial  secretion,  or  as  a  result  of  spasmodic 
closure  of  the  air-passages. 

Vasoconstricting  drugs  and  those  lessening  secretions  may  be 
used  with  advantage  in  inflammatory  conditions  in  the  lungs  with 
congestion  of  the  mucous  membrane  and  profuse  secretions.  The  best 
ones  to  use  are  volatile  substances  such  as  turpentine  and  other  vola- 
tile oils,  which  may  be  atomized  or  inhaled,  or,  especially  in  chronic 
conditions,  inhaled  in  steam.  Their  deodorizing  and  antiseptic  effects 
may  here  be  of  some  value  by  limiting  putrefaction.  This  is  espe- 
cially the  case  when  true  antiseptics,  such  as  balsam  of  Peru,  thymol, 
creosote,  etc.,  are  inhaled.  [It  has  always  appeared  questionable 
whether  such  substances  when  thus  used  actually  reach  the  inflamed 


342  PHARMACOLOGY  OF  THE  RESPIRATION 

structures  in  amounts  large  enough  to  exert  any  appreciable  antiseptic 
actions.  The  undoubted  favorable  actions  observed  clinically  would 
appear  to  be  better  explained  by  their  local  anaesthetic  and  vascular 
actions. — TR.] 

Quite  often  the  indication  is  to  render  the  secretions  more  fluid 
and  to  facilitate  their  removal, — i.e.,  to  cause  expectoration.  This  is 
the  case  when  the  secretion  is  very  scanty  or  when,  although  profuse, 
it  is  extremely  viscid,  so  that  it  is  only  with  difficulty  expelled  by 
the  actions  of  the  ciliated  epithelium  or  by  coughing.  Clinical 
experience  indicates  that  the  so-called  expectorants  often  fulfil  this 
indication  more  or  less  satisfactorily. 

EXPECTORANTS 

From  the  experimental  side  little  is  known  of  the  manner  in  which 
expectorants  act. 

The  experiments  of  Henderson  and  Taylor  and  those  of  Rossbach  and  Calvert, 
which  latter  two  are  open  to  many  objections,  are  practically  the  only  ones 
dealing  with  this  subject. 

As  stated  by  Purkinje  and  Valentin  in  1834,  the  ciliary  movements  of  the 
cells  of  the  bronchial  mucous  membrane  are  of  great  importance  for  the  removal 
of  mucus,  especially  from  the  smaller  bronchi,  in  which  coughing  cannot  produce 
any  effective  acceleration  of  the  movements  of  the  air.  However,  according  to 
Engelmann,  a  very  tenacious  thick  coating  of  mucus  opposes  an  insuperable 
obstacle  to  the  ciliary  movements,  and  only  when  the  secretion  has  become 
thinner  and  more  fluid  are  these  cells  able  to  resume  their  function,  provided 
that  they  have  not  lost  their  excitability  and  are  still  able  to  perform  them,  which 
is  not  always  always  necessarily  the  case  in  inflammations  of  the  bronchial 
mucous  membrane. 

It  is  not  known  whether  or  not  the  ciliary  movements  may  be  stimulated 
by  the  expectorants,  although  Virchow  in  1854  observed  an  active  excitation  of 
the  previously  motionless  cilia  after  a  direct  application  of  potassium  or  sodium 
hydrate  to  the  human  tracheal  mucous  membrane,  while  strong  ammonia  stopped 
the  movements  without  any  primary  stimulation.  These  two  observations  are, 
however,  of  no  significance  for  estimating  the  effect  of  medicines,  but  perhaps 
those  of  Engelmann  on  the  pharyngeal  mucous  membrane  of  the  frog  may  be  of 
some  significance.  According  to  this  author,  very  small  quantities  of  C02,  ether, 
and  ammonia  stimulate  the  ciliary  movements,  while  larger  amounts  depress  them. 

The  unstriped  bronchial  muscles  appear  to  play  a  decidedly  more  important 
r6le  in  the  transportation  of  mucus  from  the  alveoli  and  bronchioles  up  into  the 
larger  branchi,  for  there  is  no  ciliated  epithelium  in  the  alveoli  and  the  terminal 
bronchi.  Both  the  alveoli  and  the  bronchi  contain  unstriped  muscles,  whose  chang- 
ing tone  is  controlled  by  constricting  and  dilating  nervous  impulses  which  reach 
them  through  the  vagus.  This  innervation,  and,  as  will  be  seen  later,  also  the 
pharmacological  reaction  of  the  bronchial  muscles,  is  very  analogous  to  the  con- 
ditions in  the  intestine,  and  it  is  very  possible  that  these  organs  also  are  capable 
of  ascending  peristaltic  movements.  In  this  fashion  lumps  of  mucus  might  be 
moved  upward  in  the  narrowest  bronchi  (Gerlach).  Einthoven  observed  spon- 
taneous rhythmic  contractions  of  the  bronchial  muscular  apparatus  independently 
of  any  nervous  influence,  but  he  did  not  conduct  any  investigation  to  determine 
whether  these  were  always  simultaneous  contractions  of  the  whole  system  or 
whether  they  were  alternating  peristaltic  movements.  It  is  not  improbable  that 
such  peristalsis  may  be  accelerated  or  strengthened  under  the  influence  of  some 
of  the  expectorants. 

SALTS  AS  EXPECTORANTS. — All  the  salts  of  the  sodium  chloride 
group  (see  section  on  salt  action)  may  exert  some  expectorant  action 
and  increase  the  secretion  of  mucus,  for  they  are  in  part  excreted 


EXPECTORANTS  343 

by  the  bronchial  mucous  membrane  and  thus  may  bring  about  the 
secretion  of  an  increased  quantity  of  water  and  (as  occurs  whenever 
secretion  is  increased)  of  alkaline  carbonates.  This  increased  alkalin- 
ity of  the  secretion  would  be  accompanied  by  a  diminution  of  its 
viscosity,  for  the  tenacity  of  the  mucus  is  diminished  as  its  alkalinity 
rises.  In  practice  some  of  these  salts  are  much  used  for  this  purpose. 
Among  these  are  sodium  chloride  (the  waters  of  Wiesbaden  and 
many  other  springs)  and  potassium  iodide  or  potassium  sulphocya- 
nide,  which  is  not  harmful  in  thyroid  disease.  (Seep.  400  for  dangers 
of  KI  in  thyroid  patients.) 

Ammonium  chloride  appears  to  be  still  better  for  this  purpose,  for, 
following  its  administration,  traces  of  ammonium  carbonate  are 
perhaps  formed  in  the  bronchial  mucous  membrane,  and  this  has  a 
special  power  of  liquefying  mucus  and  stimulating  the  ciliary  move- 
ments. Its  use  in  combination  with  soothing  licorice  preparations 
may  therefore  be  understood.  The  alkaline  carbonates  in  Ems  water 
and  many  other  mineral  waters  act  in  a  similar  fashion. 

NAUSEANT  EXPECTORANTS 

Besides  the  salts  mentioned,  emetic  drugs,  especially  apomorphine, 
ipecac,  and  antimony  salts,  produce  a  similar  stimulation  of  the  bron- 
chial secretions  when  they  are  given  in  small  non-emetic  doses  (see 
p.  179).  This  is  probably  a  symptom  of  the  first  stage  of  their  emetic 
action,  which  causes  the  striking  increase  of  secretions  which  accom- 
panies the  nausea  induced  by  larger  doses.  With  apomorphine  the 
action  is  a  direct  one,  with  ipecac,  antimony,  etc.,  a  reflex  one,  on  the 
centres  controlling  the  secretion  of  the  bronchial  mucous  glands, 
for  these  glands  are  affected  readily,  and  often,  especially  in  children, 
even  more  readily  than  are  the  sweat-glands,  by  drugs  like  pilocarpine, 
which  are  specific  secretory  excitants. 

Moreover,  inasmuch  as  with  more  pronounced  emetic  action  the 
s  innervation  controlling  emesis  is  excited,  it  may  be  that,  in  the 
first  stages  of  their  action,  this  vagus  stimulation  may  cause  the  peri- 
stalsis in  the  smaller  bronchi  to  become  more  active.  This  may  at 
least  be  considered  as  possible. 

APOMORPHINE  HYDROCHLORIDE  in  corresponding  dosage  appears  to 
more  promptly  and  energetically  than  ipecac  or  antimony,  but  ita 
ion  seems  to  be  less  lasting.     It  may  be  given  several  times  daily 
adults  in  doses  of  2-10  mg.     Alkalies  should  be  avoided  when  this 
g  is  prescribed. 

IPECAC  may  be  administered  in  various  forms  in  dosage  of  0.05 
0.2  gm.  to  adults  and  0.01-0.1  gm.  to  children.    It  is  often  combined 
ith  opium  for  the  purpose  of  relieving  a  harrassing  cough,  but  it  is 
questionable  whether  this  combination  is  a  good  one,  for  presumably 
morphine  will  depress  the  bronchial  peristalsis  (Brodie  and  Dixon). 
ANTIMONY  AND  POTASSIUM  TARTRATE,  2-10  mg.  several  times  daily, 
y  irritate  a  susceptible  stomach  mucous  membrane.     This  is  not 


344  PHARMACOLOGY  OF  THE  RESPIRATION 

likely  to  occur  if  the  sulphate  of  antimony  be  used,  for  this  prepara- 
tion is  entirely  insoluble  in  water,  and  in  the  acid  gastric  juice  is 
changed  only  gradually  into  the  active  antimony  oxide  (see  Emetics). 
Senega  and  quillaja  bark  act  as  expectorants  in  a  fashion  not 
clearly  understood,  but  in  both  saponins  are  considered  to  be  the 
effective  constituent.  According  to  Henderson  and  Taylor,  senega 
produces  expectoration  reflexly  by  its  action  on  the  stomach,  as  do 
ipecac,  tartar  emetic,  and  ammonium  chloride. 

SAPONIN  is  a  name  given  to  a  large  number  of  non-nitrogenous  substances 
occurring  especially  in  the  bark  and  roots  of  numerous  plants.  They  are  charac- 
terized by  their  glucosidal  nature  and  by  their  property  of  aiding  in  the  formation 
of  soapsuds,  and  are  mixtures  of  various  substances  which  are  chiefly  colloidal 
and  which  have  not  yet  been  chemically  denned  (quillaic  acid,  sapotoxin,  sar- 
saparin,  parillin,  etc. ) .  As  a  general  rule,  they  are  strongly  cytotoxic  and,  when 
injected  subcutaneously,  intensely  irritating.  When  injected  intravenously,  they 
cause  haemolysis,  severe  inflammation,  enteritis  and  depression  of  the  central 
nervous  system.  The  epithelium  of  the  mucous  membrane  of  the  alimentary 
canal  is,  however,  very  resistent  to  saponin  and  completely  prevents  saponin 
poisoning,  as  it  does  not  permit  the  passage  of  altered  saponins  into  the  blood. 

The  resistance  of  the  epithelial  cells  to  saponin  has  been  especially  well 
demonstrated  by  Lhomme's  observation  that  the  ciliary  movements  in  the  frog's 
oesophagus  were  not  disturbed  by  the  application  of  concentrated  solutions  of 
saponin,  even  in  the  course  of  hours.  The  only  effect  on  the  mucous  membranes, 
therefore,  is  a  slight  irritation  of  their  sensory  secretory  mechanism.  Tickling 
and  increased  secretion  of  mucus  and  saliva  occur  when  these  substances  are 
taken  into  the  mouth  and  throat.  It  is  not  known  whether  the  increase  of 
bronchial  secretion  is  due  to  reflex  action  produced  in  this  way  or  whether  it  is 
caused  by  an  increase  tendency  to  clear  the  throat  or  to  cough.  Calvert  found 
that  the  bronchial  secretions  were  inhibited  after  the  intravenous  injection  of 
saponin,  but  such  an  experiment  is  not  at  all  adapted  to  explain  the  therapeutic 
effect  of  saponin  taken  by  mouth,  for,  when  thus  administered,  it  does  not  pass 
into  the  blood. 

Theoretically  it  is  of  interest  that  the  toxic  action  of  saponin  on  the  red 
blood-cells,  and  probably  also  on  other  animal  cells  (Ransom),  is  explained 
by  its  chemical  affinity  for  cholesterin,  the  constituent  of  the  cells  which  is 
chemically  affected  by  the  saponins.  After  saturation  with  cholesterin,  saponin 
is  no  longer  toxic  to  the  red  blood-cells,  and  consequently  the  blood-plasma, 
which  normally  contains  a  certain  amount  of  cholesterin,  protects  the  red  cells 
against  a  limited  amount  of  saponin. 

BIBLIOGRAPHY 

Brodie  and  Dixon :  Journ.  of  Physiol.,  1903,  vol.  29,  p.  97. 
Calvert:  Journ.  of  Physiol.,  1896,  vol.  20,  p.  158. 
Einthoven:    Pfliiger's  Arch.,  1892,  vol.  51,  p.  367,  lit.  here. 
Engelmann:   Hermann's  Hdb.  d.  Physiol.,  1877,  vol.  1. 

Henderson  and  Taylor:  Journ.  of  Pharmacol.  and  Exp.  Ther.,  1910,  vol.  2,  p.  153. 
Kopke:   Dissert.,  Greifswald,  1899. 
Lhomme,  M.  J.:  Th6se  Paris,  1883. 

Mayer,  L.:  Trav.  de  1'institut  Solvay,  1891,  vol.  4,  here  lit. 
Ransom:   Deut.  med.  Woch.,  1901,  No.  13. 
Rossbach:    Berl.  klin.  Woch.,  1882,  Nos.  19,  20,  27. 
Rossbach:  Wiirzburger  Festschr.,  1882,  vol.  1,  p.  85. 

PARALYSIS  AND  SPASM  OF  THE  GLOTTIS 

Normal  functioning  of  the  glottis  is  necessary  for  normal  respira- 
tion. In  paralysis  of  this  organ  a  valve-like  closure  of  the  vocal  cleft 
may  occur  during  inspiration,  while,  in  spasm  of  the  glottis,  it  is 
self-evident  that  closure  of  the  vocal  cleft  will  prevent  both  inspira- 


EXPECTORANTS  345 

tion  and  expiration.  Except  opium  or  morphine,  which  as  a  rule 
relieve  spasm  in  catarrhal  laryngitis  or  croup,  we  know  of  no  pharma- 
cological agents  which  will  directly  affect  the  laryngeal  muscles  and 
which  are  able  to  relieve  their  spasmodic  contractions. 

BRONCHIAL  SPASM 

Another  obstruction  to  the  ventilation  of  the  lungs  may  result 
from  spasm  of  the  bronchial  muscles,  usually  associated  with  the 
so-called  asthma  nervosum,  which  probably  in  most  cases  is  due  to 
an  abnormally  increased  reflex  excitability  of  the  bronchial  vagus 
centre  (Brodie  and  Dixon).  This  reflex  may  be  excited  by  stimuli  in 
the  sensory  nerves  of  diseased  bronchial,  tracheal,  and  nasal  mucous 
membranes.  As  a  result  of  the  spasmodic  contraction  of  the  smaller 
bronchi,  the  lungs  become  abnormally  distended  or  inflated,  for  in 
inspiration  the  pressure  of  the  atmosphere  can  still  overcome  the 
increased  resistance,  but  in  extirpation  the  limited  elasticity  of  the 
lungs  and  the  pressure  of  the  expiratory  muscles  are  not  sufficient  to 
do  this.  Therefore  the  quantity  of  residual  air  must  increase  with 
each  respiration. 

TREATMENT  OF  ASTHMA 

Such  an  asthmatic  attack  may  be  relieved  either  by  blunting  the 
excitability  of  the  central  reflex  mechanism — for  example,  with  chloral 
hydrate  or  similar  drugs* — or  by  depression  of  the  vagus  nerve- 
endings  in  the  bronchial  muscles.  This  latter  effect  may  be  induced 
by  inhalation  of  ether  or  chloroform,  as  Brodie's  and  Dixon's  experi- 
ments on  animals  clearly  showed,  but  this  has  not  been  therapeutically 
attempted  [?  TR.].  Bronchial  spasm  may  often  be  satisfactorily 
relieved  by  drugs  having  the  specific  power  of  rendering  the  vagus 
nerve-endings — unfortunately,  not  only  in  the  lungs — unexcitable. 

THE    ALKALOIDS    OF    THE    ATROPINE    GROUP,    AND    LOBELINE,    which 

closely  resembles  nicotine  in  its  actions  (Edmunds},  are  the  best  of 
these.  According  to  Brodie  and  Dixon,  the  action  of  atropine  is  more 
lasting  than  that  of  lobeline. 

Since  the  middle  of  the  last  century,  stramonium  leaves,  bella- 
ina,  hyoscyamus,  and  lobelia  have  been  recommended  as  remedies 
for  various  spasmodic  affections,  and  especially  for  bronchial  asthma. 
Extracts  of  these  drugs  and  the  smoke  of  their  smouldering  leaves 
or  the  salts  of  atropine  have  all  been  employed  for  this  purpose.  If 
asthma  cigarettes  exert  any  curative  action,  it  must  be  due  to  the 
small  quantities  of  atropine  salts  f  which  are  carried  along  mechani- 
cally in  the  inhaled  smoke  and  thus  reach  the  pharynx  and  lungs 
(Him  u.  Netolitzky). 

*  Urethan  is  stated  by  Brodie  and  Dixon  (loc.  eit.)  to  relax  the  bronchial 
muscles  by  a  direct  action  on  them.  If  this  be  correct,  the  drug  should  be  a 
useful  asthma  remedy,  for  its  hypnotic  action  is  comparatively  slight. 

t  According  to  Giinther,  the  smoke  of  a  cigarette  containing  4.0  gm.  of 
stramonium  leaves  contains  0.4  mg.  of  atropine. 


346  PHARMACOLOGY  OF  THE  RESPIRATION 

Atropine  (l/20-i£  mg.  several  times  a  day),  which  is  contained 
in  the  first  three  drugs  mentioned  and  its  congeners  (see  Atropine 
group,  p.  154),  as  also  lobeline,  from  Lobelia  inflata  (Indian  tobacco), 
possess  the  physiological  property  of  depressing  the  motor  nerve- 
endings  of  the  vagus  in  the  lungs,  so  that  the  bronchial  muscles  relax 
and  the  dilated  bronchi  no  longer  present  an  abnormal  resistance  to 
the  expired  air.  As  at  the  same  time  these  drugs  stimulate  the  respira- 
tory centre  (Dreser),  a  marked  improvement  and  strengthening  of  the 
respiration  follow  their  administration. 

In  addition,  excessive  bronchial  secretion,  which  often  plays  a 
part  in  exciting  attacks  of  asthma,  is  lessened  by  these  drugs.  When, 
however,  sudden  vasomotor  disturbances,  such  as  congestion  of  the 
bronchial  mucous  membranes,  are  responsible  for  the  attack, — as,  for 
example,  in  the  asthma  of  hay  fever, — these  drugs,  as  may  be  well 
understood,  are  without  effect.  [As  a  matter  of  fact,  the  asthma  in 
hay  fever  is  probably  due,  in  part  at  least,  to  spasm  of  the  bronchial 
muscles,  which  may  be  secondarily  caused,  and  clinical  experience 
has  demonstrated  that  marked  relief  is  often  obtained  by  the  use  of 
atropine  or  similar  drugs  in  asthma  of  this  type. — TR.] 

It  is  claimed  that  opium  smoking  and  the  inhalation  of  the  smoke 
from  smouldering  paper  impregnated  with  saltpetre  are  of  value  in 
bronchial  asthma.  Such  smoke  contains  varying  quantities  of  car- 
bonates and  nitrites  in  addition  to  the  usual  gases  present  in  smoke. 
Under  some  conditions  a  favorable  influence  may  be  expected  from 
the  nitrites,  but  this  will  hardly  be  the  case  in  bronchial  asthma, 
the  condition  now  under  discussion.  This  will  be  more  likely  to 
occur  in  angina  pectoris,  which  is  occasionally  mistaken  for  bronchial 
asthma.  [Here  again  clinical  experience  is  not  altogether  in  accord 
with  the  opinion  of  the  author.  The  translator  is  confident  that  he 
has  occasionally,  though  rarely,  seen  unmistakable  relief  secured  by 
the  use  of  nitrites  in  cases  of  undoubted  bronchial  asthma. — TR.] 

[EPINEPHRIN. — The  marked  relief  following  the  subcutaneous  in- 
jection of  epinephrin  (0.5-0.7  mg.)  in  asthma  is  so  striking  and  well 
known  that  it  should  be  mentioned  here.  Plethysmographic  experi- 
ments, completed  in  1911  in  the  laboratory  of  H.  Meyer,  demonstrate 
that  this  drug  causes  an  excitation  of  the  sympathetic  nerve-endings 
here  just  as  in  other  organs  (see  p.  141)  and  produces  a  relaxation  of 
the  bronchial  muscles.  A  number  of  blood-pressure  observations  made 
on  such  patients,  by  the  translator  and  by  I.  7.  Lemann,  have  shown 
that  the  relief  of  the  asthmatic  attack  following  the  injection  of 
•epinephrin  is  not  necessarily  accompanied  by  any  rise  in  the  blood- 
pressure.  As  a  matter  of  fact,  the  blood-pressure  occasionally  rises, 
but  more  often  remains  constant  or  falls.  The  fall  in  blood-pressure, 
when  it  does  occur,  is  apparently  due  to  the  relief  of  the  dyspnoea 
and  cyanosis.  It  has  been  claimed  by  various  authors  that  the  oral 
administration  of  epinephrin  also  affords  relief  in  asthma.  The  trans- 
lator from  his  own  experience  can,  however,  report  only  failures  tc 


EXPECTORANTS  347 

confirm  these  statements.  In  a  number  of  cases,  after  oral  adminis- 
tration had  failed  to  give  any  relief,  the  subcutaneous  administration 
promptly  stopped  the  attack.  Unfortunately,  in  several  of  the  author's 
cases,  after  frequent  repetition  of  the  administration  during  a  num- 
ber of  months,  the  treatment  became  ineffectual. — TR.] 

[IODIDES. — No  discussion  of  the  pharmacology  of  asthma  or  bronchial  spasm 
is  complete  which  does  not  include  some  consideration  of  the  action  of  iodides 
in  these  conditions.  Clinical  experience  has  demonstrated  that  in  a  large  pro- 
portion of  cases  of  true  bronchial  asthma  the  daily  ingestion  of  fifteen  to  thirty 
grains  of  iodide  of  potash  results  in  a  more  or  less  pronounced  and  unmistakably 
beneficial  effect  on  the  frequency  of  the  attacks.  While  some  of  this  benefit 
might  be  explained  as  the  result  of  the  expectorant  action  of  the  iodide  (see 
p.  343),  there  is  another  probable  explanation  of  it  which,  as  far  as  the 
translator  has  been  able  to  learn,  has  not  yet  been  suggested.  As  will  be  dis- 
cussed later  (p.  354  ff.)  the  thyroid  gland  exerts  an  active  effect  on  the  sympathetic 
system,  perhaps  in  the  sense  that  it  acts  as  a  hormone  on  the  chromaffinnic 
organs.  Further,  it  is  established  that,  at  any  rate  under  many  conditions,  the 
administration  of  the  iodides  causes  an  increase  in  the  functional  activity  of 
the  thyroid.  Consequently  it  appears  at  least  plausible  that  the  favorable  effects 
of  the  regular  ingestion  of  iodides  are  to  be  attributed  to  an  increased  sympa- 
thetic tone  brought  about  through  increase  of  thyroid  function.  Otherwise  ex- 
pressed it  might  be  stated  that  the  daily  use  of  iodides  may  in  this  respect  have 
similar  effects  to  the  constant  administration  of  minimal  doses  of  epinephrin, 
which  we  have  just  seen  is  a  most  efficient  means  of  relieving  the  condition  of 
bronchial  spasm.  A  further  pharmacological  deduction  would  be  that  possibly 
the  administration  of  thyroid  substance  would  be  a  more  direct  way  of  attaining 
this  end.— TB.] 

BIBLIOGRAPHY 

Brodie  and  Dixon:  Transact.  Pathol.  Soc.,  London,  1903,  vol.  54. 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  26,  p.  237. 

Edmunds:   Amer.  Journ.  Physiol.,  1904,  vol.  11,  p.  79. 

Einthoven:    Pfliiger's  Arch.,  vol.  51. 

Giinther:   Wien.  klin.  Woch.,  1911,  p.  748. 

Him  u.  Netolitzky,  Wien.  klin.  Woch.,  1903,  p.  583. 

3.  Disturbance  in  the  circulation  in  the  lungs,  such  as  stasis  re- 
sulting from  cardiac  insufficiency,  may  markedly  interfere  with  the 
respiration  and  cause  dyspnoea.  The  blood  accumulating  in  the 
pulmonary  capillaries  distends  them  and  causes  rigidity  of  the  lungs 
(v.  Basck's  "Lungenstarre"),  the  power  of  excursion  of  the  lungs 
being  diminished  so  that  the  renewal  of  air  is  seriously  interfered 
with.  The  increased  CO2  tension  in  the  blood-vessels  resulting  from 
this  condition,  then  in  its  turn  causes  subjective  dyspnoea  with  violent 
but  ineffectual  attempts  to  breathe.  In  cases  of  cardiac  insufficiency 
the  respiratory  disturbances  may  be  relieved  by  the  relief  of  the 
disturbances  of  compensation  resulting  from  the  administration  of 
drugs  of  the  digitalis  group. 

The  acute  dyspnoea  of  exertion,  such  as  occurs  with  healthy 
hearts  after  running,  mountain  climbing,  etc.,  may  be  prevented 
by  small  doses  of  caffeine,  0.25  gm.,  taken  about  two  hours  before- 
hand (Parisot). 

BIBLIOGRAPHY 

v.  Basch:  Arbeiten,  1892  and  1896,  vols.  2  and  3. 
isot:  These  de  Paris.  1890. 


CHAPTER  X 

PHARMACOLOGY  OF  THE  RENAL  FUNCTION 
PHYSIOLOGY  OF  DIURESIS 

THE  renal  secretion  of  the  healthy  mammal  is  an  albumen-free, 
dilute  aqueous  solution  of  the  products  of  metabolism  and  of  sub- 
stances which  after  penetrating  into  the  body  are  not  utilized  or 
retained  but  simply  pass  through  it. 

AVAILABLE  WATER  NECESSARY  FOR  THE  SECRETION  OF  URINE. — The 
first  condition  necessary  for  the  formation  and  excretion  of  urine  is  the 
presence  of  available  water, — i.e.,  water  which  may  be  given  up  by  the 
blood.  As  the  normal  water  content  of  the  blood  is  retained  with 
great  tenacity,  it  is  essential  that  there  be  a  certain,  although  slight, 
excess  of  water  in  the  blood,  a  temporary  hydraemia,  if  the  giving  up 
of  water — i.e.,  diuresis — is  to  occur. 

In  the  blood-plasma  the  water  is  combined  with  its  dissolved  crystalloids 
and  with  colloids  ( proteids )  in  a  state  analogous  to  that  of  the  "  Quellungs  " 
water,  i.e.,  intramolecularly  imbibed  water,  in  a  gel  or  jelly.  Just  as  in  a 
jelly,  a  certain  portion  of  the  "  Quellungs  "  water  of  the  blood  may  be  readily 
squeezed  out  by  pressure.  As,  however,  the  concentration  of  the  proteid  increases 
the  tenacity  of  the  combination  between  the  water  and  the  proteid,  the  "  Quel- 
lungs "  pressure,  rapidly  rises,  and  very  quickly  becomes  so  great  that  even  the 
highest  pressure  possibly  available  in  the  kidney  can  squeeze  no  water  out  of 
the  blood.  Superfluous  water,  introduced  with  food  or  entering  the  blood  from 
the  various  cavities  of  the  body  and  .from  the  tissues,  is  under  ordinary  conditions 
readily  excreted.  In  case  these  sources  fail  to  supply  extra  water,  a  very  small 
portion  of  the  water  normally  present  in  the  blood  may  be  excreted,  but  the 
kidneys  can  under  no  conditions  excrete  what  remains. 

Importance  of  Sufficient  Blood-pressure. — It  may  be  considered 
as  established  that  the  water  of  the  urine  is  excreted  chiefly  in  the 
vascular  loops  of  the  glomeruli.  For  this  to  occur,  the  blood-pressure 
in  them  must  be  sufficient  to  overcome  not  only  the  hydrostatic  pres- 
sure in  the  uriniferous  tubules  and  ureters,  but  also  the  combination 
between  the  water  and  the  dissolved  colloids,  the  "Quellungs"  pres- 
sure, of  the  blood-plasma.  Under  normal  conditions,  according  to 
Starling,  this  equals  about  30  mm.  Hg,  and,  as  a  matter  of  fact, 
urinary  secretion  usually  ceases  when  the  blood-pressure  falls  much 
below  40  mm.,  and,  within  physiological  limits,  increases  almost  pro- 
portionately with  the  rising  blood-pressure  (Goll).  (See  Fig.  49.) 

If,  on  the  other  hand,  the  blood  is  artificially  made  markedly 
hydnemic,  its  "Quellungs"  pressure  becomes  low  or  practically 
zero.  This  occurs,  for  example,  during  the  continuous  intra- 
venous infusion  of  isotonic  sodium  chloride  solution,  and  under 
these  conditions  water  may  be  secreted  in  the  urine  with  a  minimal 
348 


349 


blood-pressure,  which  is  just  sufficient  to  maintain  the  blood  flow 
(Gottlieb  u.  Magnus).  The  process  is  therefore  fundamentally  com- 
parable to  a  filtration  or  a  transudation. 

THEORY  OF  URINARY  SECRETION 

This  conception  forms  the  essential  portion  of  Ludwig's  theory  of  urinary 
excretion,  and  was  first  deduced  by  Bowman  from  anatomical  facts  and  later  by 
Ludwig  from  the  above-mentioned  experimental  data.  According  to  it,  in  the 
glomeruli  there  is  expressed  from  the  blood  a  "  colloid-free "  nitrate  containing 
water  and  dissolved  crystalloids  such  as  urea,  salts,  etc.  As  this  passes  down 
through  the  uriniferous  tubules  it  undergoes  a  concentration,  the  water  being 
reabsorbed  into  the  blood  by  osmotic  action,  which  flows  from  the  glomeruli  to 
the  thick  network  of  capillaries  surrounding  the  tubules. 

On  account  of  a  number  of  objections,  Heidenheim  has  offered,  as  a  substi- 
tute to  this  essentially  mechanical  conception,  the  so-called  secretion  theory, 
according  to  which  the  water  is  not  expressed  from  the  blood  as  a  result  of  pres- 
sure, but  is  secreted  by  a  specific  cell  activity,  while  the  solid  constituents  are 
actively  secreted  by  the  epithelium  of  the  uriniferous  tubules  in  a  manner 
analogous  to  that  in  which  the  secretion  of  other  true  glandular  epithelium 
occurs. 


FIG.  40. — VS=vagus  stimulation;  V—  venesection;  /=infusion  of  blood;  C=closure,  and 
O=  opening  of  the  carotid  and  crural  arteries.  Urinary  excretion  in  dog  under  varying  blood- 
pressure  (Goll). 

Heidenheim's  conception  provides  without  difficulty  for  all  the  phenomena 
observed  in  normal  and  altered  renal  secretion,  explaining  everything  by  an 
adaptation  of  the  kidney  to  the  needs  of  the  organism.  It  renounces,  however, 
any  attempt  to  analyze  the  process,  and  especially  any  attempt  to  differentiate  the 
influence  which  may  be  exerted  on  the  excretion  of  urine  by  varying  physiological 
or  pathological  conditions.  Such  are,  for  example,  the  effect  of  diuretics,  such  as 
the  salts,  calomel,  caffeine,  etc. 

The  functional  processes  of  all  other  glands  of  the  body  are  independent  of 
direct  physical  and  of  almost  all  chemical  influences.  They  are  specific  processes, 
directly  or  reflexly  under  nervous  control,  and  may  be  analyzed  chiefly  in  respect 
to  their  dependence  on  nervous  control.  On  the  other  hand,  we  know  of  no 
specific  innervation  for  the  kidney,  but  we  do  know  that  there  are  certain  physical 
factors,  dependent  on  the  composition  of  the  blood  and  on  its  circulation  through 
the  kidneys,  which  are  of  decisive  importance  for  its  activity. 

However,  the  investigations  of  the  last  decade  have  clearly  shown 
that  the  formation  of  the  urine  cannot  yet  be  completely  or  even  in 
greater  part  explained  physicochemically. 


350  PHARMACOLOGY  OF  RENAL  FUNCTION 

It  will  therefore  be  our  task  to  find  out  how  far  we  may  follow,  or 
recognize  as  possibly  effective,  the  influence  of  physical-chemical  fac- 
tors on  the  secretion  of  urine  under  abnormal  conditions  (for  example, 
alteration  of  the  renal  circulation},  and  especially  on  the  alterations 
of  function  resulting  from  the  action  of  pharmacological  agents,  and 
to  learn  how  far  on  the  other  side  we  must  assume  specific  secretory 
processes  which  are  not  susceptible  to  further  analysis. 

The  Importance  of  the  Amount  of  Blood  Flowing  through  the 
Kidney. — If  the  blood  flows  slowly  through,  the  glomerular  vessels  (on 
account  of  low  pressure  or  decided  resistance),  or  should  it  stagnate 
there, — as,  for  example,  when  the  renal  veins  are  ligated, — the  secre- 
tion of  urine  ceases,  even  though,  in  the  later  case,  the  pressure  in  the 
glomerular  loops  must  rise  to  its  maximum.  This  fact  was  especially 
brought  forward  by  Heidenheim  as  an  objection  to  the  theory  of 
pressure  nitration  and  advanced  as  an  argument  for  the  correctness 
of  the  secretory  theory.  However,  the  filtration  theory  demands,  be- 
sides an  adequate  blood-pressure,  that  the  blood  flow  in  these  vessels 
shall  be  rapid  enough  to  supply  to  them  constantly  fresh  blood  in 
sufficient  quantities,  for  otherwise  the  blood,  stagnating  in  the  glome- 
ruli,  must,  on  account  of  loss  of  its  available  water,  necessarily  in- 
stantly become  so  concentrated  that  its  "Quellungs"  pressure  will 
rise  so  high  that,  even  under  any  attainable  blood-pressure,  no  appre- 
ciable amounts  of  water  may  be  expressed,  and  the  secretion  of  urine 
must  therefore  cease.  Diuresis,  therefore,  under  all  conditions  de- 
mands an  adequately  rapid  changing  of  the  blood  in  the  glomerular 
vessels, — i.e.,  an  adequate  circulation  of  blood  through  the  kidneys. 
It  is  apparent  that  this  factor  is  of  even  greater  moment  for  diuresis 
than  is  the  blood-pressure. 

Excretion  of  Urea,  NaCl,  etc.,  in  the  Glomeruli. — Most  of  the 
crystalloids  dissolved  in  free  form  in  the  blood  do  not  cause  any 
appreciable  osmotic  resistance  to  the  passage  of  the  urinary  fluid 
through  the  walls  of  the  glomeruler  loops  (see  p.  384  ff.),  and  therefore 
do  not  hinder  the  excretion  of  water.  On  the  contrary,  diuresis 
generally  increases  when  larger  amounts  of  these  substances  are  con- 
tained in  the  blood  (Tamman).  From  this  it  is  necessarily  deduced 
that  these  substances  are  excreted  in  the  glomeruli  together  with,  and 
at  the  same  tune  as,  the  water  (Hermann,  Treskin,  Richet,  Loewi, 
Magnus).  As  a  matter  of  fact,  their  excretion  rises  and  falls  almost 
proportionately  with  the  amounts  of  water  excreted,  they  being  appa- 
rently swept  along  with  it. 

Pathological  Retention  of  Salts. — However,  what  has  been  said 
above  is  subject  to  an  important  limitation,  for  in  experiments  on 
animals  it  has  often  been  observed  that,  in  long-continued  experiments 
in  which  intravenous  saline  infusion  has  been  given  to  cause  diuresis, 
the  diuresis  after  a  time  diminishes  and  the  kidney  retains  more  and 
more,  not  only  of  the  water  but  also  of  the  sodium  chloride  infused. 


PHYSIOLOGY  OF  DIURESIS  351 

Moreover,  it  is  well  known  that  in  certain  pathological  conditions  in 
man,  chlorides  are  very  sparingly  excreted,  and  that  the  administration 
of  salt,  instead  of  increasing  diuresis  as  it  does  normally,  actually 
decreases  it  (Widal  and  Javal,  Griiner,  Schlayer,  Hadinger  and. 
Takayasen,  and  a  review  in  v.  Noorden's  Pathology  of  Metabolism, 
vol.  1). 

Impaired  Permeability  of  the  Glomerulus. — In  order  to  understand 
this  phenomenon  we  must,  in  our  consideration  of  the  nitration  theory, 
add  to  it  the  almost  self-evident  premise  that  the  permeability  of  the 
living  filter  membrane  in  the  glomeruli  for  free  crystalloids  or  ions  is 
neither  unchangeable  nor  without  limitation,  but  that,  on  the  contrary, 
the  size  of  the  hypothetical  pores  changes  under  different  nervous, 
mechanical,  or  direct  chemical  influences,  and  that  therefore  many 
substances  in  solution  can  pass  through  them,  sometimes  more  and 
sometimes  less  readily  and  sometimes  not  at  all. 

It  is  well  known  that  the  permeability  of  this  membrane  for  proteid  is  subject 
to  variations.  Under  normal  conditions  proteid  does  not  pass  through  the  human 
kidney  in  appreciable  amounts,  but  under  certain  conditions  very  slight  changes 
in  the  circulation  are  sufficient  to  render  the  glomeruli  permeable  to  albumen. 
This  occurs,  for  example,  in  orthostatic  albuminuria  (Jehle).  Moreover,  experi- 
mental analogies  for  the  variable  permeability  of  filters  are  not  lacking.  For 
example,  filters  impregnated  with  gelatin  are  rendered  more  or  less  permeable 
for  different  substances,  according  to  the  gelatin  concentrations  used  (Bechhold). 

Secretion  by  the  Tubular  Epithelium. — "While  the  excretion  of 
many  of  the  soluble  constituents  of  the  urine  in  general  occurs  as  a 
result  of  physical  phenomena,  it  is  known  that  the  secretion  of  some 
other  substances,  among  them  uric  acid  and  many  salts  of  the  heavy 
metals,  occurs  in  a  different  fashion  and  does  not  appear  to  stand 
in  any  recognizable  relationship  with  the  amounts  of  urine  excreted. 
Apparently  they  are  excreted  by  the  functional  activity  of  the  epi- 
thelium of  the  tubules.  Their  secretion  must  therefore  be  considered 
as  due  to  a  secretory  activity  incapable  of  closer  analysis,  just  as  is 
the  case  with  secretions  in  other  true  glands. 

Concentration  of  the  Glomerular  Filtrate. — The  urine  flowing  from 
the  kidney  is  usually  more  concentrated  than  a  true  filtrate  from 
the  glomeruli  could  possibly  be.  This  higher  concentration  is,  how- 
ever, readily  comprehensible  if  in  the  secretory  theory  it  is  premised 
that  the  solid  constituents  of  the  urine,  including  urea  and  the  salts, 
are  secreted  by  the  uriniferous  tubules  and  mixed  in  with  the  dilute 
glomerular  filtrate.  As  qualitatively  and  quantitatively  this  secretion 
is  constantly  changing  with  the  needs  of  the  organism  and  the  momen- 
tary condition  of  the  secreting  cells,  a  varying  composition  of  the 
urine  is  to  be  expected.  As,  however,  as  was  mentioned  above,  the 
crystalloids  appear  in  the  urine  in  quantities  nearly  proportional  to> 
the  amounts  of  water,  and  as  their  excretion  by  physical  means  (such 
as  filtration  or  transudation  in  the  glomeruli)  may  be  considered  as 

Wished,  it  would  be  necessary  to  assume  the  occurrence  of  an 


352  PHARMACOLOGY  OF  RENAL  FUNCTION 

additional  secretion  of  the  same  crystalloids  by  the  epithelial  cells  of 
the  tubules  in  order  to  bring  about  the  final  concentration.  This  com- 
plicated hypothesis  need,  however,  not  be  adopted  if  it  be  assumed 
that  the  concentration  of  the  urine  is  brought  about  by  a  reabsorption 
of  water,  similar  to  that  which  takes  place  in  the  large  intestine 
during  the  concentration  of  its  liquid  contents. 

In  the  human  alimentary  canal  about  4000  c.c.  of  water  are  secreted  in  every 
24  hours,  and  of  this  about  3900  c.c.  are  reabsorbed.  In  order  to  secrete  about 
30  gm.  of  urea  in  24  hours,  50  litres  of  fluid  must  be  filtered  in  the  glomeruli 
from  blood  containing  about  0.6  per  cent,  of  urea,  and  of  this  about  48  litres  must 
be  reabsorbed  in  the  long,  sinuous  course  of  the  uriniferous  tubules.  Between 
500  and  600  litres  of  blood  flow  through  the  kidneys  in  24  hours,  of  which  about 
one- tenth  would  have  to  be  expressed  as  a  filtrate  to  satisfy  the  Ludwig  hypothesis, 
There  is  nothing  improbable  in  such  an  assumption.  On  the  contrary,  the 
appreciably  narrower  lumen  of  the  vas  deferens  as  compared  with  that  of  the 
vas  aiferens  may  be  considered  as  a  proof  that  a  considerable  portion  of  the 
fluid  of  the  blood-plasma  entering  the  glomerulus  is  removed  in  some  fashion, — 
in  other  words,  is  excreted. 

Selective  Reabsorption. — The  reabsorption  of  water  in  the  tubules 
cannot  be  explained  physicochemically  any  more  than  that  of  certain 
of  its  crystalloid  constituents.  However,  numerous  earlier  investiga- 
tions *  rendered  it  probable,  while  the  most  recent  observations 
(NisJii)  have  certainly  proven  that  the  tubules  are  able  to  absorb  not 
only  water  but  also  dissolved  substances,  especially  the  readily  dif- 
fusible crystalloids. 

The  normal  urine  of  rabbits  and  dogs  contains  no  recognizable  amounts  of 
sugar.  In  accordance  with  this,  Nishi  found  that  normally  the  medullary  portions 
of  the  kidney  contained  no  sugar,  while  it  was  constantly  present  in  the  cortical 
portion,  but,  if  in  any  fashion  glycosuria  were  induced,  sugar  was  found  in  the 
medullary  portions.  Inasmuch  as  the  minimal  amounts  of  sugar  contained  in 
the  blood  could  not  influence  the  quantitative  determination  of  the  sugar  present 
•in  kidneys  from  which  the  blood  had  been  thoroughly  removed,  these  observations 
permit  the  conclusion  that  sugar  is  excreted  in  the  cortex,  but  that  under  normal 
conditions  it  disappears  again  in  the  medulla  and  that  it  is  reabsorbed  there. 
Only  when  larger  amounts  are  excreted  in  the  glomeruli  and  when  the  reabsorp- 
tion is  incomplete  does  sugar  appear  in  the  urine  (Pollak). 

COMBINED  EFFECT  OF  FILTRATION,  SECRETION,  AND  REABSORPTION. — 
In  any  case  it  may  be  maintained  that,  generally  speaking,  the  extent 
of  the  filtration  taking  place  in  the  glomeruli  determines  the  total 
quantity  of  the  urine  secreted,  while  the  momentary  composition  of 
the  urine  is  determined  by  a  selective  secretion  or  reabsorption  in  the  i 
tubules. 

Secretion  of  Water  ~by  the  Tubules. — In  addition  to  this  power  of 
free  absorption,  the  tubules  probably  also  possess  the  faculty  of  excret- 
ing water  under  some  conditions  and  adding  this  to  the  glomerular 
filtrate.  This  would  appear  to  be  analagous  to  the  behavior  of  the 
sweat-glands,  which  also  excrete  almost  pure  water  in  amounts  which 
vary  according  to  their  blood  supply  and  the  water  content  of  the 

*  v.  Sobieranski,  Halsey  and  Meyer,  Cushny,  Loewi,  Gottlieb  and  Magnus, 
Griinwald,  Sollmann;  see  latter  for  lit. 


PHYSIOLOGY  OF  DIURESIS 


353 


blood.  The  secretion  of  a  very  dilute  urine,  the  osmotic  concentration 
of  which  does  not  equal  that  of  the  blood,  which  is  observed  after  free 
drinking  of  water,  in  diabetes  insipidus,  etc.,  can  hardly  be  explained 
on  any  other  assumption  (Prey).  Moreover,  there  can  be  no  doubt 
that  there  is  a  certain  antagonism  in  the  behavior  of  the  capillary 
system  of  the  glomeruli,  which  is  supplied  by  the  vasa  afferentia 
of  the  renal  artery,  and  the  capillary  system  of  the  tubules,  which 
receive  their  supply  from  the  vasa  efferentia  and  the  arteriolae  rectae. 
If  the  vasa  afferentia  dilate,  the  vasa  efferentia,  and  perhaps  also  the 
arteriolge  rectas,  contract.  Thus  the  pressure  and  flow  in  the  glome- 
ruli are  increased  while  in  the  tubular  capillaries  they  are  relatively 
diminished,  and  vice  versa.  In  accordance,  therefore,  with  such  varia- 
ble conditions,  nitration  in  the  glomeruli  or  secretion  in  the  tubuli 
may  preponderate  (see  Fig.  41). 

It  is  self-evident  that  both  of  these  vascular  systems  are,  like  all 
other  blood-vessels,  under  the  control  of  the  nervous  system,  but 
we  have  little  exact  knowledge  of  this  mechanism.  The  oncometric 
determination  of  the  volume  of  the  kidney  serves  as  a  means  of  esti- 


Arl. 


ArterioTa,  reef. 

Fio.  41. 

lating  the  blood  flow  through  it,  if  the  outflow  of  venous  blood 
id  of  urine  be  unhindered.  Further,  the  color  of  the  venous  blood 

lows  an  approximate  estimation,  for  with  increased  blood  flow  the 
lood  appears  light  red  through  the  wall  of  the  vein,  while  with  dimin- 

led  blood  flow  the  blood  appears  darker. 

According  to  Tigerstedt,   during  moderate  diuresis  blood  amounting  to  80 
cent,  of  the  kidney  weight  flows  through   it  in  one  minute;    with   greater 

iresis  as  much  as  140  per  cent.     If  both  kidneys  weigh  300  gin.,  this  would 

lount  in  man  to  345-600  kg.  in  24  hours. 

BIBLIOGRAPHY 

echhold:  Ztschr.  f.  phys.  Chem.,  1907,  vol.  60. 
Butschli:   Bau  quellbarer  Korper,  etc.,  1896,  p.  24. 
Cushny:  Journ.  of  Phys.,  1901,  vol.  27. 
Frey:   Pfluger's  Arch.,  1906,  vol.  112. 
Frey:  Pfluger's  Arch.,  1911,  vol.  139,  p.  435. 
Goll:  Ztschr.  f,  ration.  Med.,  1854,  N.F.,  vol.  4,  p.  86. 
Gottlieb  u.  Magnus:   Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45. 
Griiner:  Jahrb.  f.  Kinderh.,  1906,  vol.  64. 
Griinwald:   Arch.  f.  exp.  Path.  u.  Pharm.,   1909,  vol.  60. 
Hadinger  u.  Takayasen:  Deut.  Arch.  f.  klin.  Med.,  1891. 
Halsey  u.  Meyer:  Marburg.  Sitzungsber.,  Juli,  1902. 
Hermann:  Sitzungsber.  d.  Wien.  Akad.,  1859,  vol.  36. 
23 


354  PHARMACOLOGY  OF  RENAL  FUNCTION 

Jehle:  Die  lordotische  Albuminurie,  Wien,  1909. 

Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48,  p.  410. 

Magnus:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45. 

Nishi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  329. 

v.  Noorden's  Path.  d.  Stoffw.,  1906,  vol.  1,  p.   1003. 

Pollak:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  157. 

Richet:  Trav.,  1893,  p.  198. 

Schlayer:  Pfliiger's  Arch.,  1907   ( Urannephritis ) . 

v.  Sobieranski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  35. 

Sollmann,  T.:    Am.  J.  of  Phys.,  1902,  vol.  8,  p.  155,  here  lit. 

Starling:  Journ.  of  Physiol.,  1899,  vol.  24,  p.  317. 

Tamman:   Ztschr.  f.  physikal.  Chem.,  1896,  vol.  20. 

Widal  et  Javal:  Compt.  rend,  de  la  Soc.  Biol.,  1903. 

FACTORS  CONTROLLING  DIURESIS 

These  factors  mentioned  as  being  of  moment  for  diuresis, — namely, 

Hydraemia,  with  its  influence  on  "Quellungs"  pressure  and  the 
osmotic  tension  of  the  blood; 

Blood-pressure  and  rapidity  of  the  blood  flow  in  the  renal 
vessels ; 

Reabsorption  and  secretion  in  the  tubules,  may  be  pharmaco- 
logically influenced  at  times  in  common  and,  in  so  far  as  they  do  not 
depend  upon  one  another,  at  times  separately. 

Alteration  of  the  Water  Content  of  the  Blood 

1.  Hydraemia  necessarily  results  from  drinking  liquids  or  eating 
food  containing  much  water.  The  water  which  is  drunk  dilutes  the 
blood  to  a  moderate  degree  (Buntzen)  and  is  excreted  in  the  urine  in 
the  course  of  6-7  hours  (Falck),  and,  as  water  containing  carbonic  acid 
is  absorbed  more  quickly  (see  p.  173) ,  it  is  excreted  more  rapidly.  After 
this  has  occurred  the  amount  of  water  in  the  body  remains  the  same  as 
it  was  previously,  for  diuresis,  thus  stimulated,  results  only  in  a 
washing  out  of  the  body  and  a  dilution  of  the  urine.  Such  dilution 
of  the  blood  may  be  beneficial  in  chronic  poisonings  and  in  conditions 
of  abnormal  metabolism,  while  increased  diuresis  may  be  useful  in 
disease  of  the  urinary  tract,  such  as  pyelonephritis,  cystitis,  or  uratic 
concretions. 

It  is  clear  that  the  same  indication  may  be  met,  in  case  of  need,  by 
subcutaneous  or  intravenous  administration  of  isotonic  saline  solution. 

If,  on  the  contrary,  it  is  desirable  to  remove  water  from  the  body 
by  causing  increased  diuresis,  the  necessary  hydraBmia  must  be 
obtained  at  the  expense  of  the  water  contained  in  the  tissues.  A 
transudation  of  the  lymph-plasma  into  the  blood  will  do  this,  for 
the  lymph  contains  only  about  one-third  as  much  proteid  as  does  the 
blood-plasma.  This  occurs,  for  example,  after  extensive  blood  letting, 
which  may  therefore  have  a  diuretic  effect  (Leube,  Geelmuyden, 
Laache}. 

The  Production  of  Hydreemia  ~by  the  Use  of  Salts. — The  osmotic 
tension  of  the  blood  may  be  increased  by  the  administration  of  sub- 
stances which  penetrate  through  the  cell  membranes  only  slowly  or 


HYDR^MIA  AS  CAUSE  OF  DIURESIS  355 

not  at  all,  thus  attracting  the  water  from  the  tissues  into  the  lymph 
and  blood.  This  is  another  means  which  may  be  employed  to  produce 
hydrasmia.  It  is  a  self-evident  prerequisite  for  the  value  of  this  pro- 
cedure that  the  substances  employed  can  readily  pass  through  the 
glomerular  membranes  and  thus  do  not  oppose  any  osmotic  resistance 
to  filtration  at  this  point.  If  they  then  pass  into  the  tubules  with 
the  water  from  the  blood,  they  will,  by  their  osmotic  pressure,  prevent 
the  reabsorption  of  the  water,  in  this  way,  too,  increasing  the  amount 
of  urine. 

" The  diuretic  salt  action,"  according  to  this  conception,  is  then 
produced  in  two  fashions, — first  by  causing  hydraemia,  and  second 
by  inducing  a  "diarrhoea  in  the  tubules."  Probably  a  third  factor 
is  active  here,  an  "  Entquellung"  *  of  the  blood-plasma  by  the  salts, 
the  blood  colloids  being  thus  deprived  of  some  of  their  water,  which 
water  is  rendered  more  readily  filterable  by  being  freed  from  the 
"Quellungs"  pressure  which  opposes  the  filtration  (Hoppe-Seyler, 
Euneberg}.  Colloids  like  gum  arabic  or  gelatin  (0.6-1.0  gm.  per  kilo) , 
when  injected  intravenously,  inhibit  diuresis,  but  if  sodium  chloride 
be  subsequently  injected,  free  diuresis  occurs  as  a  result  of  the 
"Entquellung"  of  the  colloids.  Moreover,  the  flow  of  blood  through 
the  renal  vessels  is  facilitated  by  addition  of  salt  to  the  blood,  for  the 
renal  tissues  shrivel  up  somewhat  as  a  result  of  losing  part  of  their 
water;  thus  the  lumen  of  the  blood-vessels  becomes  wider  (Sollmann). 

The  diuretic  effect  of  the  salts  is,  other  things  being  equal,  inversely 
proportional  to  their  power  of  diffusion.  As  a  matter  of  fact,  the 
immediate  diuretic  effect  when  solutions  of  the  but  slightly  diffusible 
Na2S04  or  NaHC03  are  introduced  into  the  blood  is  markedly  greater 
than  occurs  after  injection  of  equal  amounts  of  isosmotic  solutions 
of  NaCl  or  sodium  nitrate,  which  diffuse  much  more  readily  into  cell 
branes  (Halsey,  Magnus,  Gushing,  Munzer,  and  others). 

In  such  experiments,  as  should  be  expected,  the  poorly  diffusing 
sodium  sulphate  is  excreted  in  larger  amounts  and  with  greater 
rapidity  than  is  the  readily  diffusible  sodium  chloride.  In  other 
words,  it  is  more  "harnfahig"f  than  NaCl,  for  during  the  relatively 
long  passage  through  the  uriniferous  tubules  the  Na2So4  is  absorbed 
to  a  much  slighter  extent  than  is  the  NaCl.  Diuresis  caused  by  Na2SO4, 
therefore,  is  more  intense  and  passes  off  more  rapidly  than  that  caused 
by  NaCLJ 

For  practical  use,  however,  only  substances  relatively  easily  ab- 
sorbed from  the  intestines — i.e.,  of  the  salts,  only  the  readily  diffusible 
ones,  especially  NaCl  and  potassium  nitrate  and  acetate — may  be 

*  By  this  apparently  untranslatable  German  term  is  meant  the  attraction 
to  and  combination  with  the  salts  of  a  portion  of  the  water  previously  firmly 
combined  with  the  colloids  of  the  plasma. 

t  Harnfahig  means  readily  excreted  in  the  kidney. 

t  [Sodium  sulphate  has  a  greater  power  of  attracting  the  water  from  its  com- 

.tion  with  proteid  and  consequently  causes  a  greater  hydraemia. — TB.] 


356  PHARMACOLOGY  OF  RENAL  FUNCTION 

administered  for  this  indication.*  Of  these  the  acetate  after  absorption 
is  changed  in  the  blood  into  the  less  diffusible  and,  therefore,  diureti- 
cally  more  active  carbonate.  This  would  appear  to  account  for  the 
preference  given  it  as  a  diuretic. 

CONTRAINDICATIONS. — It  is  necessary,  however,  again  to  emphasize 
the  fact  that  in  many  cases  of  disease  the  administration  of  sodium 
chloride  does  not  increase  but,  on  the  contrary,  diminishes  the  secre- 
tion of  urine,  even  though  the  blood  is  rendered  more  hydraBmic  as 
a  result  of  the  attraction  of  water  into  it  from  the  tissues,  which 
occurs  when  the  sodium  chloride  in  the  blood  is  increased.  In  such 
cases  it  would  appear  that  the  glomerular  membrane  has  become 
relatively  impermeable  for  NaCl,  and  that  therefore  this  salt  offers 
an  osmotic  resistance  to  the  excretion  of  water;  here,  by  administer- 
ing a  diet  poor  in  salt,  the  osmotic  partial  pressure  of  this  salt  may 
be  lowered  and  an  increased  urinary  secretion  result  (Nils  Finsens). 

Urea  as  a  Diuretic. — The  same  effect  may  also  be  obtained  at 
times  by  the  administration  of  substances  which  act  like  salts  but 
for  which  the  glomerular  membrane  is  still  permeable, — for  example, 
by  the  administration  of  urea,  of  which  10  gm.  are  approximately 
isosmotic  with  5  gm.  NaCl  or  8  gm.  potassium  acetate.  According 
to  this,  it  would  be  necessary  to  administer  at  least  20-40  gm.  of  urea 
daily  to  produce  a  pronounced  effect  (Klemperer) .  Urea,  while 
passing  readily  through  the  intestinal  epithelium  and  permeating 
rapidly  into  the  blood-cells,  passes  into  the  muscle-cells  and  the  epi- 
thelial membrane  of  the  urinary  tract  with  great  difficulty  (Gryns, 
Overton).  In  the  blood  and  tubules,  therefore,  it  has  a  strong  power 
of  attracting  water  to  itself.  Such  elective  semi-permeability  is  often 
met  with  in  the  organism,  although  it  cannot  be  explained  chemically. 

Sugars  as  Diuretics. — Glucose,  and,  in  a  greater  degree,  the  poorly 
diffusing  milk-sugar,  when  taken  in  amounts  of  100-200  gm.  dis- 
solved in  as  little  water  as  possible,  are  stated  to  cause  diuresis 
and  absorption  of  oedema.  When  they  pass  into  the  blood,  they  cause, 
presumably  by  osmotic  action,  a  temporary  hydraemia  (Meilach).  If 
they  pass  into  the  urine,  as  in  diabetes  mellitus,  they  must,  like  the 
salts,  hinder  reabsorption  in  the  tubules  and  produce,  as  it  were, 
a  "renal  diarrhoea." 

Mercury  as  a  Diuretic. — Finally,  hydreemia  may  be  induced  by 
mercurial  preparations,  especially  by  calomel,  of  which  doses  of  0.2 
gm.,  several  times  daily,  produce  a  marked  diuresis,  especially  if  the 
tissues  are  oedematous  and  diarrhoea  is  prevented  by  opium. 

According  to  Fleckseder  (unpublished  experiments),  the  hydrasmia 
caused  by  calomel  is  induced  as  follows :  The  increased  secretions  and 
the  partially  prevented  reabsorption  in  the  small  intestine,  together 
with  the  actively  stimulated  peristalsis,  cause  the  accumulation  in  the 

*  [M.  Fisher  believes  that  the  saline  cathartics  as  ordinarily  administered  are 
absorbed  in  sufficient  amounts  to  cause  a  hydrsemia  and  thus  to  cause  increased 
diuresis. — TB.] 


FACTORS  INFLUENCING  RENAL  CIRCULATION      357 

large  intestine  of  large  amounts  of  fluid.  If  this  large  quantity  of 
fluid  is  not  rapidly  expelled  from  the  colon,  but  remains  there  for  a 
time,  it  is  absorbed  by  the  mucous  membrane  of  the  large  intestine 
and  dilutes  the  blood,  which  in  the  meantime,  by  attracting  water 
from  the  oadematous  tissues  to  replace  that  lost  to  the  intestine,  has 
already  regained  its  original  concentration.  The  blood  which,  has 
thus  been  rendered  hydnfimic  then  gets  rid  of  its  extra  water  through 
the  kidneys,  and  a  marked  diuresis  occurs. 

The  diuretic  effect  of  the  mercurials  appears  not  to  depend  at  all 
on,  nor  to  be  related  in  any  way  to,  the  very  harmful  action  exerted 
on  the  renal  epithelium  by  its  soluble  preparations,  such  as  corrosive 
sublimate. 

BIBLIOGRAPHY 

Bauer:   Ztschr.  f.  Biol.,  1872,  vol.  8. 

Buntzen:  Om  Ernaringen,  etc.,  Kopenhagen,  1879. 

Falck:   Ztschr.  f.  Biol.,  1872,  vol.  8. 

Finsens,  Nils:    Krankheit,  Therap.  d.  Gegenw.,  July,  1905. 

Geelmuyden :  Dubois'  Arch.,  1892. 

Gryns:   Pfluger's  Arch.,  1896,  vol.  63. 

Handowsky:   Fortschr.  in  d.  Colloidchemie  der  Eiweisskb'rper.,  Dresden,  1911. 

Hoppe-Seyler :   Virchow's  Arch.,  1856,  vol.  9,  p.  260. 

Klemperer:   Berl.  klin.  Woch.,  1896. 

Laache:  Die  Aniimie,  1897. 

Leube:  Pentzold's  Hdb.,  vol.  7,  p.  250. 

Lillie,  R.:    Am.  Journ.  of  Physiol.,  vol.  20,  1907,  No.  1. 

Ludwig:  Lehrb.,  vol.  2,  p.  428. 

Magnus:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45,  pp.  23  and  25. 

Meilach:   These  de  Paris,  1889. 

Overton:    Z.  f.  physikal.  Ch.,  1897,  vol.  22,  p.  189. 

Pribram,  E.:   Colloid-chem.  Beihefte,  1910,  vol.  2,  Nos.  1  and  2. 

Pugliese:  Ztschr.  f.  Biol.,  1910,  vol.  54. 

Runeberg:   Deut.  Arch.  f.  klin.  Med.,  1884,  vol.  35,  p.  266. 

Sollmann :    Am.  Journ.  of  Physiol.,  vol.  9,  p.  454. 

Strubell:    Der  Aderlass,  Berlin,  1905,  lit.  here. 

2.  The  rate  of  flow  and  the  pressure  of  the  blood  in  the  renal 
ssels  depends,  on  the  one  hand,  on  the  resistance  in  them  and,  on 
e  other,  on  the  functional  performance  of  the  heart  and  on  the 
;neral  blood-pressure. 

STASIS. — The  resistance  to  the  blood  flow  in  the  kidney  may  be 
hindered  outflow  from  the  renal  veins,  as,  for  example,  in  cardiac 
sis,  in  which  case  an  improvement  of  the  cardiac  function  relieves 
the  oliguria  (see  p.  296).  The  outflow  from  the  renal  veins  may  also 
be  hindered  by  a  collection  of  fluid  in  the  abdominal  cavity,  and, 
if  the  fluid  be  removed  by  aspiration,  the  previously  halting  secretion 
of  urine  may  become  normal  again.  Further,  if  the  amount  of  fluid 
in  the  abdomen  be  diminished  by  other  means, — for  example,  by  the 
removal  of  large  amounts  of  water  by  way  of  the  intestines,  as  a 
t  of  the  administration  of  Epsom  salts  or  of  drastic  cathartics, 
by  excessive  sweating, — the  pressure  on  the  vena  cava  is  lessened 
d,  as  a  rule,  improved  diuresis  results.  In  this  indirect  sense, 
thartics  and  sudorific  drugs  may,  under  pathological  conditions, 


358  PHARMACOLOGY  OF  RENAL  FUNCTION 

increase  the  secretion  of  urine,  -in  place  of  diminishing  it  as  they  do 
under  normal  conditions  [see  footnote,  p.  356. — TR.]. 

RENAL  VASOCONSTEICTION. — Resistance  to  the  blood  flow  through 
the  kidney  may  also  be  due  to  a  more  or  less  pronounced  contraction 
of  the  renal  arteries  and  capillaries. 

Our  knowledge  of  the  variations  in  the  tone  of  the  renal  vessels 
is  very  imperfect.  Sensory  stimuli,  especially  those  arising  in  the 
urinary  tract,  not  infrequently  cause  long-continued  reflex  anuria, 
which  probably  is  due  to  a  tonic  contraction  in  some  portion  of  the 
renal  vascular  system,  whether  in  the  glomerular  vessels  or  in  the 
vasa  efferentia  or  in  the  capillaries  is  uncertain.  Moreover,  in  many 
forms  of  acute  nephritis  with  scanty  secretion  of  urine,  it  is  possible 
that  the  abnormal  contraction  of  individual  groups  of  the  renal  vessels 
may  be  the  cause  of  the  oliguria.  Finally,  it  is  conceivable  that  the 
calibre  of  the  uriniferous  tubules  may  change  and  under  some  con- 
ditions oppose  a  high  resistance  to  the  passage  of  urine.  The  richness 
of  the  nerve  supply  in  their  membrana  propria  (Disse}  speaks  for 
the  possibility  that  this  may  occur. 

Indirectly  the  amount  of  bloofl.  flowing  through  the  kidney  may  be  roughly 
estimated,  and  the  degree  of  resistance  may  be  directly  determined  by  the  use 
of  the  oncometer  if  care  be  taken  to  prevent  any  hindrance  to  free  outflow  of 
the  venous  blood  and  urine;  but  this  method  gives  no  information  about  the 
distribution  of  the  blood  in  the  different  renal  vessels.  It  is  possible,  too,  that 
dilatation  of  the  vessels  and  the  resulting  increased  blood  flow  may  occur  without 
any  increase  in  the  volume  of  tl\e  kidney,  this  occurring  at  the  cost  of  other 
compressible  parts  of  the  kidney — for  example,  of  the  tubules — or  as  a  result 
of  an  "  Entquellung "  or  shrinking  of  the  capillary  epithelium  (Sollmann). 
Consequently  the  rate  of  the  blood  flow  through  the  kidney  may  not  under  all 
conditions  be  deduced  from  the  changes  in  its  volume  (Loewi). 

The  renal  vessels  may  be  contracted  as  a  result  of  reflexes  from 
sensory  stimuli,  especially  those  resulting  from  cooling  of  the  skin 
(Wertheimer).  Drugs  which,  like  strychnine,  increase  the  reflex 
tone  of  the  vasomotor  centres,  may  also  cause  constriction  of  the 
renal  vessels.  However,  this  centrally  induced  vasoconstriction  in 
the  kidney  is  not  a  lasting  one,  being  much  less  persistent  than  the 
constriction  of  the  intestinal  vessels,  and  after  a  short  time  the  renal 
vessels  again  dilate.  The  blood  forced  from  the  other  still  contracted 
vascular  systems  will  then  flow  so  much  the  more  freely  through  the 
kidney,  and  an  active  diuresis  results.  The  effect  of  the  renal  vasodi- 
latation  following  such  reflex  renal  vasoconstriction  is  evidenced  by  the 
desire  to  urinate  which  is  often  experienced  after,  or  even  during,  a 
cold  bath.  The  peripheral  action  of  epinephrin  appears  to  produce 
a  similar  effect  in  the  kidney.  [With  pituitrin  this  effect  is  still  more 
pronounced. — TR.  ] 

RENAL  VASODILATATION 

Chemical  influences  of  varying  nature  may  cause  dilatation  of  the 
renal  vessels  J>y  a  direct  action  on  their  walls. 

Hydrwmia  of  any  type  causes  a  dilatation  of  the  renal  vessels, 


RENAL  VASODILATORS  359 

and  therefore  all  agents  causing  hydraemia  indirectly  produce  this 
effect. 

It  has  been  found  that  with  the  occurrence  of  hydrasmia,  no  matter 
how  occasioned,  the  volume  of  the  kidney  is  regularly  increased,  and 
that  the  blood  flows  through  it  more  rapidly  and  that,  too,  even  after 
the  kidney  vessels  have  been  isolated  from  central  nervous  influences 
by  destruction  of  their  nerves.  Therefore,  it  would  appear  that  the 
amount  of  water  in  the  blood — or,  otherwise  expressed,  the  "Quel- 
lungs"  pressure  of  the  blood — exerts  a  direct  influence  on  the  tone 
of  the  renal  vessels  and  in  this  way  regulates  the  blood  flow  through 
the  kidney  in  a  purposeful  manner  (Loewi) . 

ALMOST  ALL  SUBSTANCES  WHICH  ARE  EXCRETED  BY  THE  KIDNEY 
CAUSE  DILATATION  OF  ITS  VESSELS  (Abeles,  Grutzner). — The  kidney 
is  the  excretory  organ  for  most  of  those  substances  which  simply  pass 
through  the  body.  Just  as  the  intestine,  in  order  rapidly  to  rid  the  body 
of  many  harmful  substances,  reacts  to  them  with  hydrsemia  of  the 
mucous  membrane,  diminished  absorption,  increased  peristalsis,  and, 
in  case  of  more  powerful  irritation,  with  free  transudation,  it  would 
appear  that  almost  all  the  substances  foreign  to  the  body  which  must . 
be  excreted  by  the  kidney  cause  active  vasodilatation  in  this  organ  and 
increased  diuresis.  Many  of  these  substances  also,  even  in  very  small 
amounts,  cause  degenerative  changes  in  the  kidney,  and  thus,  in  spite 
of  their  powerful  primary  diuretic  effect,  are  not  useful  practically 
or  are  perhaps  directly  harmful.  Cantharidin,  formerly  much,  used 
in  the  treatment  of  dropsy,  acts  in  this  fashion. 

Other  substances  cause  these  degenerative  changes  only  when  they 
reach  the  kidney  in  large  quantities  or  in  high  concentration,  but  are 
ordinarily  harmless  and  may  be  used  as  mild  kidney  stimulants.  In 
this  group  belong  many,  perhaps  all,  of  the  so-called  ethereal  oils, 
which  are  present  in  very  small  amounts  in  numerous  drugs  and 
which  may  well  be  responsible  for  the  diuretic  action  attributed  to 
many  of  them.  Some  of  the  substances  mentioned  above  as  inducing 
hydrasmia,  especially  urea,  and  perhaps  also  potassium  nitrate,  appear 
also  to  possess  a  similar  direct  vasodilating  action  and  the  power  of 
accelerating  the  blood  flow  in  the  kidneys. 

Those  narcotics,  such  as  alcohol,  amylene  hydrate,  paraldehyde, 
etc.,  which  are  excreted  by  the  kidneys,  may  produce  similar  effects, 
but  with  them  their  specific  narcotic  action,  which  includes  their  power 
of  lessening  reflex  actions,  may  also  be  of  importance,  especially  in 
cases  of  reflex  anuria  (Mori). 

BIBLIOGRAPHY 

Abeles:  Wien.  Sitz.-Ber.,  1883,  vol.  87. 

Disse:  Marburger  Sitzungsberichte,  1898. 

Griitzner:   Pfliiger's  Arch.,  1875,  vol.  11. 

Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  53. 

Mori:  Arch.  f.  Hygiene,  1888,  vol.  7,  p.  354. 

Sollmann:  Am.  Journ.  Physiol.,  1903,  vol.  9,  p.  454. 

Wertheimer:  Arch,  de  Physiol.,  1893. 


360  PHARMACOLOGY  OF  RENAL  FUNCTION 

SPECIFIC  RENAL  VASODILATING  DRUGS 

Substances  belonging  to  the  purine  group,  caffeine,  theobromine, 
and  related  substances,  dilate  the  renal  vessels  in  an  entirely  peculiar 
and  elective  fashion. 

CAFFEINE,  or  theine,  trimethylxanthine,  occurs  in  the  following 
proportions  in  various  plants: 

In  coffee  bean,  up  to  2  per  cent.;  in  tea  leaves,  up  to  4  per  cent.;  in  cola 
nut,  up  to  2  per  cent.;  in  guarana,  up  to  5  per  cent.;  and  in  Paraguay  tea  and 
other  plants,  in  still  larger  proportions  ( Goris  et  Fluteaux ) .  In  pure  state  it 
forms  shining  silky  crystals,  very  soluble  in  boiling  water,  but  at  15°  C.  requiring 
80  parts  for  their  solution.  In  its  chemical  constitution  it  closely  resembles 
theobromine  and  its  isomer,  theophylline,*as  also  xanthine  and  uric  acid,  while 
synthetic  chemistry  has  furnished  a  number  of  other  closely  related  substances. 
All  these  substances  are  substitution  products  of  the  purin  nucleus. 

Nr=CH  NH— CO  NH— CO 

CHC— NHV                    CO      C— NH\                CO     C— NH\ 
||       II            >CH                |          II            >CO            |  \CH 

N— C N^  NH— C-NH/  NH— C N^ 

Purine  Uric  acid  Xanthine 

CHj  N CO  NH— CO  CHa  N— CO 

I           I          /CH,  I          |         /CH,              |       | 

CO      C— N<  CO      C— N<                     COC— NH\ 

|          II        >CH  |          H        >CH                                  \CH 

CH,N C— N^  CH3N C— N^  CH3  N— C N^ 

Caffeine  Theobromine  Theophylline 

The  diuretic  effect  of  coffee,  tea,  and  caffeine  has  long  been  known 
and  used  in  therapeutics  (Bouchardat,  1859).  For  a  long  time  the 
views  concerning  the  manner  in  which  it  caused  diuresis  were  very 
contradictory.  Some  authorities — as,  for  example,  Riegel — as  late 
as  in  1884  considered  this  to  be  an  indirect  action  similar  to  that  of 
digitalis,  while  others,  among  them  Curschmann  in  1885  and  Bronner 
in  1886,  as  a  result  of  their  clinical  observations,  pronounced  the 
caffeine  diuresis  to  be  independent  of  any  cardiac  and  vascular  action 
and  attributed  it  to  a  specific  stimulation  of  the  kidney. 

CAFFEINE 

It  has  already  been  stated  that  caffeine  exerts  a  marked  influence 
on  the  circulation,  but  this  effect  is  entirely  different  from  that  of 
digitalis,  consisting  of  the  following  factors : 

1.  Stimulation  of  the  yasomotor  centres  causing  constriction  of 
the  arterioles,  and,  as  a  result,  at  times,  an  increase  in  the  blood- 
pressure. 

2.  An  influence  on  the  cardiac  function  in  four  different  ways: 
(a)   Stimulation  of  the  inhibitory  vagus  centre,  causing  retardation 
of  the  pulse,      (b)   Stimulation  of  the  cardiac  accelerating  ganglia 
in  the  periphery,  causing  acceleration  of  the  pulse;  one  or  the  other 
of  these  two  effects  preponderating  as  conditions  or  individuals  may 

*  The  widely-advertised  theocin  is  a  synthetic  theophylline. — TB. 


FACTORS  CONTROLLING  DIURESIS 


361 


differ,  (c)  An  effect  on  the  heart  muscle,  the  relaxing  power  being 
diminished  while  the  contractile  energy  is  increased;  as  a  result 
usually  a  diminution  of  the  pulse  volume  of  the  heart  and  a  fall  in 
blood-pressure,  (d)  Dilatation  of  the  coronary  vessels. 

If  the  vasoconstriction  is  the  preponderating  effect,  the  blood- 
pressure  rises  above  the  normal;  but  if  the  vasoconstricting  centres 
are  less  excitable  than  usual  or  if  they  have  been  paralyzed  by  pharma- 
cological agents  such  as  alcohol,  caffeine,  as  a  rule,  lowers  the  blood- 
pressure.  However,  in  neither  case  would  the  actions  of  caffeine  cause 
an  increase  of  the  blood  flow  through  the  kidney  or  an  increased 
diuresis  resulting  therefrom,  for,  in  case  the  blood-pressure  is  raised 
by  caffeine,  this  is  due  not  to  acceleration  of  the  blood  flow 
throughout  the  body  but  to  its  retardation,  just  as  is  the  case  with 
strychnine.  Therefore,  only  when  the  insufficient  blood  flow  through 


C  7m  uri  ne 


dry. 


od- 


sol 


hlor 


Ra 


al  h  yd? 


1. 


0.02 


0.02 


0.01  caffeine 


FIQ.  42. — Effects  of  caffeine  on  the  blood-pressure  and  renal  secretion 
in  the  chloralized  rabbit  (v.  Schroder). 

the  kidney  and  the  halting  diuresis  is  due  to  the  fact  that  the  heart 
is  beating  feebly,  and  therefore  insufficiently  supplying  its  coronary 
vessels  with  blood,  can  the  general  circulatory  action  of  caffeine  cause 
an  increase  in  the  secretory  activity  of  the  kidney. 

DIRECT  ACTION  ON  THE  KIDNEY. — However,  even  when  the  heart 
is  entirely  healthy  and  receiving  the  optimal  amount  of  blood,  caffeine 
acts  as  a  diuretic.  To  v.  Schroder  belongs  the  credit  of  having  been 
the  first  to  prove  experimentally  that  caffeine  diuresis  depends  essen- 
tially on  a  specific  action  in  the  kidney,  by  showing  that  its  diuretic 
effects  may  actually  be  diminished  and  under  some  conditions  entirely 
suppressed  by  the  stimulation  of  the  vasoconstrictor  centres  by  caffeine, 
while,  on  the  other  hand,  marked  diuresis  occurs  when  these  centres 
have  been  depressed  by  chloral,  paraldehyde,  and  similar  drugs,  or 
when  their  influence  on  the  renal  vessels  has  been  prevented  by  section 

the  renal  nerves. 


362 


PHARMACOLOGY  OF  RENAL  FUNCTION 


tfabbit 

0,  OlfMbrph.  mur*. 


f* 


Rost's  investigations  demonstrated,  moreover,  that  the  diuretic 
effect  occurs  only  when  considerable  amounts  of  caffeine  pass  into  the 
urine,  and  that  consequently  its  seat  of  action  lies  in  the  renal  paren- 
chyma itself.  In  dogs,  in  which  diuretic  effects  are  obtained  only  by 
very  large  doses  of  caffeine,  only  8  per  cent,  of  the  caffeine  adminis- 
tered passes  into  the  urine,  while  in  rabbits,  which  react  to  relatively 
small  doses  with  marked  diuresis,  more  than  20  per  cent,  is  excreted. 
Although  v.  Schroder  explained  the  diuresis  caused  by  caffeine 
as  due  to  stimulation  of  the  secretory  elements  of  the  kidney  to 
greater  activity,  it  has  not  been  possible  to  prove  that  such  a  specific 
stimulation  of  secretory  activity  occurs.  In  fact,  its  occurrence  has 
Been  rendered  improbable  by  the  experiments  of  Loewi,  who  found 
that  during  phloridzin  glycosuria  caffeine  increased  the  amount  of 
urine  secreted  six-  or  sevenfold,  while  there  was  no  increase  in  the 
amounts  of  sugar  excreted,  although  the  sugar  is  undoubtedly  excreted 

by  a  specific  secretory  activity  of  the  kid- 
ney. On  the  other  hand,  there  are  two 
other  factors  definitely  established  which 
are  sufficient  to  account  for  the  stimula- 
tion of  renal  secretions  by  caffeine.  These 
are,  in  the  first  place,  an  increased  flow  of 
blood  in  the  kidney  and,  secondly,  an  in- 
hibition of  reabsorption  in  the  uriniferous 
tubules. 

INCREASED  BLOOD  FLOW. — Caffeine 
and  other  related  substances  under1  all 
conditions  cause  a  dilatation  of  certain  of 
the  renal  vessels,  so  that,  as  a  rule,  the 
total  volume  of  the  kidney  is  increased,  as 
can  be  shown  by  the  use  of  the  oncometer. 
However,  even  when  the  volume  of  the  kidney  does  not  increase  of  its 
own  accord,  or  when  it  is  kept  at  a  constant  volume  by  firm  encapsula- 
tion, it  may  be  demonstrated  that  the  blood  flow  through  the  kidney 
is  markedly  augmented  by  caffeine,  for  the  blood  in  the  renal  veins 
which  was  previously  dark  in  color  now  has  the  color  of  arterial  blood 
{Loewi,  Fletcher,  Henderson  u.  Loewi}.  This  effect  is  independent 
of  the  renal  nerves,  for  it  occurs  even  many  weeks  after  their  division 
and  must  therefore  be  due  to  an  action  on  the  muscles  in  the  walls  of 
the  renal  vessels.  By  such  an  actively  augmented  blood  flow  through 
the  kidney  the  necessary  conditions  for  increased  diuresis  are  estab- 
lished. In  accordance  with  this,  it  has  been  found  that  caffeine 
produces  no  effect  on  diuresis  if  the  chief  blood  paths — that  is,  the 
vessels  of  the  glomerular  loops — are  diseased  and  incapable  of  react- 
ing, and  that  caffeine  diuresis  may  still  occur  if  the  pathological 
changes  have  affected  essentially  only  the  tubular  epithelium 
(Schlayer). 


0.04  Caffeine 

Flo.  43. — Effects  of  caffeine  on 
the  secretion  of  the  normal  right  and 
the  nerveless  left  kidney. 


CAFFEINE  GROUP  363 

The  second  factor,  the  inhibited  reabsorption,  has  not  been  abso- 
lutely proven,  but  has  been  shown  to  be  extremely  probable. 

INHIBITION  OF  RE  ABSORPTION. — Evidence  of  this  reabsorption  was  long 
ago  furnished  by  the  staining  experiments  of  Sobieranski,  who  found  that  under 
the  influence  of  caffeine  the  epithelium  of  the  convoluted  tubules  lost  the  power 
of  imbibing  and  staining  with  indigo-carmine,  which  after  injection  into  the 
blood  is  excreted  in  large  amounts  in  the  urine  and  which  under  normal  conditions 
is  absorbed  by  these  cells  and  stains  them  deeply. 

These  experiments  indicated,  in  the  first  place,  that  this  stain,  although 
excreted  in  the  urine,  did  not  pass  into  it  through  the  tubular  epithelium,  and, 
in  the  second  place,  that  when  caffeine  had  been  administered  this  stain  could 
no  longer  pass  with  the  reabsorbed  fluid  into  the  epithelial  cells  as  it  does  nor- 
mally. Otherwise  the  nuclei  would  be  intensely  stained  after  caffeine  just  as  is 
the  case  under  normal  conditions.  It,  therefore,  would  appear  that  caffeine 
inhibits  reabsorption  by  lessening  the  power  of  the  tubular  epithelium  to  reabsorb 
substances  from  the  glomerular  filtrate. 

Further  support  for  this  view  is  furnished  by  the  experiments  of  Hirokawa, 
who  found  the  osmotic  pressure  in  the  renal  cortex  very  constant  but  varying 
within  wide  limits  in  the  medulla,  and  that,  in  exact  proportion  to  the  concen- 
tration of  the  urine  last  secreted,  it  was  many  times  higher  here  than  in  the 
cortex.  Under  the  influence  of  caffeine,  however,  the  molecular  concentration  in 
the  medulla  sinks  nearly  to  the  level  of  that  in  the  cortex.  This  is  to  be  ex- 
plained most  simply  by  the  assumption  that  the  cortical  secretion  or  filtrate 
remains  unconcentrated,  which  is  equivalent  to  saying  that  the  normal  concen- 
trating reabsorption  of  the  urinary  water  fails  to  take  place  in  the  medullary 
portion.  The  observations  of  Galeotti  and  Santa,  that  only  the  cortical  portion 
and  not  the  straight  tubules  hypertrophy  when  compensatory  hypertrophy  of 
one  kidney  occurs,  would  indicate  that  the  medullary  portion — that  is  to  say, 
the  straight  tubules — have  no  important  secretory  function.  (For  lit.  see 
Kapsammer. ) 

Grilnwald's  observations  on  the  excretion  of  the  chlorides  also  point  in  the 
same  direction.  He  found  that  rabbits  poor  in  chlorides,  which  secrete  urine 
containing  no  chlorides,  may,  by  the  administration  of  theobromine,  be  made  to 
excrete  them  in  the  urine  in  such  large  amounts  that  they  may  die  because  of 
the  loss  of  chlorides.  Moreover,  the  chloride  content  of  the  renal  cortex,  the  place 
where  the  chlorides  are  excreted,  was  found  to  be  very  constant  and  almost  the 
same  in  animals  whether  they  were  rich  or  poor  in  chlorides,  while  the  chloride 
content  of  the  cortex  was  found  to  vary  parallel  with  the  chloride  content  of  the 
urine  and  to  be  regularly  increased  when  theobromine  is  administered.  It  appears 
that  this  is  most  probably  due  to  the  fact  that  theobromine  causes  a  diminished 
reabsorption  of  the  chlorides  in  the  medullary  portion  of  the  kidney. 

OTHER  ACTIONS  OF  CAFFEINE. — Besides  acting  on  the  circulation 
and  on  the  renal  function,  caffeine  increases  the  general  reflex  excita- 
bility of  the  central  nervous  system  and  augments  the  functional 
capacity  of  the  striated  muscles.  ( See  appropriate '  sections. )  The 
increased  reflex  excitability  may  be  observed  in  both  cold-  and  warm- 
blooded animals  after  very  moderate  doses,  while  in  severe  poisoning 
in  animals  it  may  cause  a  reflex  tetanus.  In  man  the  lesser  degrees 
of  this  action  express  themselves  by  excitement,  sleeplessness,  marked 
palpitation,  and  sometimes  also  by  diarrhoea  and  vomiting  (Kursch- 
mann). 

As  A  DIURETIC. — Caffeine,  in  doses  of  0.1-0.3  gm.  several  times 
daily  (0.5  gm.  maximal  single  dose  and  1.5  gm.  maximal  dose  for 
24  hours),  or  the  readily  soluble  double  salt  caffeine  and  sodium  sali- 
cylate,  may  cause  very  marked  diuretic  effects,  provided  that  the 


364  PHARMACOLOGY  OF  RENAL  FUNCTION 

tissues  or  the  body  cavities  contain  sufficient  fluid  as  in  cases  of  oedema 
or  exudation  [provided  also  that  the  kidney  is  not  so  damaged  that  it 
cannot  react  efficiently. — TR.]. 

In  individuals  with  readily  excitable  vasomotor  centres  the  diuretic 
effects  of  caffeine  may  be  expected  to  be  uncertain,  for  it  stimulates 
these  centres  in  a  fashion  analogous  to,  but  much  more  weakly  than, 
strychnine,  and  this  central  action  may  counteract  the  local  vasodilat- 
ing  action  in  the  renal  arteries.  In  such  cases  combination  with 
alcohol  or  similarly  acting  drugs  may  aid  in  producing  the  desired 
effect. 

The  diuretic  action  of  theobromine  and  theophylline,  which  are 
chemically  so  closely  related  to  caffeine,  is  even  more  reliable  than 
that  of  caffeine,  for  they  cause  hardly  any  central  stimulation. 

THEOBROMINE  is  very  insoluble  in  water,  and  is  therefore  advan- 
tageously administered  in  the  soluble  but  very  alkaline  double  salt 
theobromine  and  sodium  salicylate,  diuretin,  in  doses  of  0.5-1.0  gm. 
(6.0  gm.  per  diem),  or  as  theobromine  and  sodium  acetate,  known  as 
agurin,  in  like  dosage.  Disturbances  of  the  stomach  and  intestines  are 
more  readily  caused  by  these  drugs,  however,  than  by  caffeine. 

Theophylline,  or  theocin,  is  stated  to  be  an  even  more  powerful 
diuretic,  especially  in  doses  of  from  0.2-0.5  gm.,  but  it  readily  causes 
disturbances  of  the  stomach,  vomiting  and  diarrhoea,  and  in  doses  of 
1.0  gm.  per  diem  has  occasionally  caused  violent  epileptic  attacks  in 
epileptic  patients  (Schlesinger) .  Not  more  than  0.8  gm.  of  the  pure 
theophylline  or  1.5  gm.  of  its  sodium  acetate  should  be  administered 
daily. 

As  theobromine  and  theophylline  also  exert  the  same  peculiar  action  on  the 
striated  muscles  as  caffeine,  one  might  be  tempted  to  believe  that  the  muscle  action 
and  the  diuretic  action  are  in  some  way  due  to  a  common  cause.  The  parallelism 
of  these  two  actions  is,  however,  only  an  accidental  one,  and  is  not  observed  in  a 
whole  series  of  other  synthetically  prepared  purine  derivatives.  Thus,  acetyl- 
amidocaffeine,  diacetylamidocaffeine,  and  caffeine  methylendiamin  hydrochlorate 
possess  no  action  on  the  muscles  and  are  in  other  respects  practically  without 
toxic  action,  while  they  exert  the  specific  diuretic  action  in  a  high  degree 
(H.  Meyer,  unpublished  experiments). 

In  conclusion  one  more  important  point  should  be  emphasized. 
While  all  so-called  irritant  diuretics,  spices,  ethereal  oils,  cantharides, 
metallic  salts,  and  even  concentrated  salt  solutions,  when  administered 
subcutaneously  damage  the  kidney  and  cause  albuminuria,  the  drugs 
of  the  caffeine  group  cause  no  pathological  alterations  in  the  kidney, 
even  when  they  are  administered  repeatedly  in  large  or  even  in  poison- 
ous doses.  They  may,  therefore,  be  administered  during  long  periods, 
and  even  in  the  presence  of  parenchymatous  nephritis,  with  less  risk 
than  any  other  diuretics.  It  is  even  possible  that  the  improved  blood 
flow  to  the  kidney  may  exert  a  beneficial  effect  on  the  diseased  organ 
(Loewi) . 


DIGITALIS  AS  A  DIURETIC  365 

BIBLIOGRAPHY 

Albanese:  Arch.  f.  exp.  Path.  u.  Pharm.,  1894,  vol.  34. 
Bondzynski  u.  Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  36. 
Fletcher,  Henderson  u.  Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  53. 
Galeotti  u.  Santa:  Ziegler's  Beitriige,  1902,  vol.  31. 
Goris  u.  Fluteaux:   Bull,  science  Pharm.,  1910,  vol.  17,  p.  599. 
Griinwald:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 
Hirokawa:  Hofmeister's  Beitrage,  1908,  vol.  11. 

Kapsammer:  Nierendiagnostik  u.  Nierenchirurgie,  1907,  vol.  2,  p.  560  ff.  literat. 
Koschlako:  Virchow's  Arch.,  1864,  vol.  31. 
Kurschmann:   Deut.  Klinik,  1893. 
Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48. 
Loewi:  Marburger  Sitz.-Ber.,  1904. 
Loewi:  Wien.  klin.  Woch..  1907,  No.  1. 
Meyer,  H.:  Marb.  Sitz.-Ber..  1902. 

Rost:  Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  36,  p.  18. 
Schlayer:  Verb.,  d.  Kongr.  f.  inn.  Med.,  1906. 
Schlesinger:  Munch,  med.  Woch.,  1905,  No.  23. 
v.  Schroder:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  22,  p.  39. 
Sobieranski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  35. 

EFFECTS  OF  THE  DIGITALIS  SUBSTANCES  ON  THE  RENAL 
BLOOD  FLOW 

The  members  of  the  digitalis  group  resemble  the  purine  bodies  in 
one  particular, — that  is,  in  their  power  actively  to  dilate  the  renal 
vessels. 

While  it  is  well  known  that  the  most  important  therapeutic  prop- 
erty of  this  group  is  their  power  of  improving  a  pathologically  weak- 
ened heart  function  and  in  this  way  increasing  diuresis  indirectly  by 
improving  the  general  circulation,  it  was  emphasized  by  Lauder- 
Brunton  and  Power,  as  early  as  1874,  that  digitalis  may  act  as  a 
diuretic  even  in  normal  men  in  whom  the  heart  function  is  an  optimal 
one.  It  may  also  be  shown,  as  has  recently  been  done  by  Loewi  and 
Jonescu,  that  increased  diuresis  occurs  in  the  normal  healthy  animal 
after  digitalis  and  especially  after  doses  so  small  as  to  cause  no  rise 
in  the  blood-pressure.  Under  these  conditions  the  oncometer  shows 
that  there  is  a  marked  increase  in  the  volume  of  the  kidney,  indicating 
dilatation  of  the  vessels  and  increased  flow  of  blood  through  it.  In 
accordance  with  this  is  the  fact,  long  known  by  clinicians,  that  digitalis 
increases  the  diuresis  in  cardiac  patients  and  causes  a  disappearance 
of  oedema,  usually  without  increasing  the  blood-pressure,  and  often 
in  fact  when  the  pulse  is  markedly  slowed  and  the  pressure  in  the 
large  arteries  decidedly  diminished. 

This  action  of  digitalis  on  the  renal  vessels  is  a  purely  local  one, 
for  it  also  occurs  in  a  kidney  which  has  been  deprived  of  its  nerves. 
In  this  particular  digitalis  acts  in  the  same  way  as  caffeine  and  its 
congeners.  As,  however,  digitalis  does  not  appear  to  exert  the  second 
diuresis-producing  action  of  caffeine,  the  inhibition  of  reabsorption, 
its  direct  diuretic  effect  is  only  slight  as  compared  with  that  of 

caffeine. 

BIBLIOGRAPHY 

Lauder-Brunton  and  Power:   Zentralbl.  f.  med.  Wiss.,  1874. 
Loewi  u.  Jonescu:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59. 


366  PHARMACOLOGY  OF  RENAL  FUNCTION 

3.  SECRETION  AND  REABSORPTION  IN  THE  TUBULES 

Whether  or  not  it  is  possible  by  the  use  of  pharmacological  agents 
to  cause  or  to  increase  the  excretion  of  water  by  the  tubular  epithelium 
is  not  known  with  certainty  (Frey}. 

The  limitation  of  the  reabsorption  of  water  in  the  tubules,  which 
may  be  considered  as  analogous  to  diarrhoea  in  the  intestines,  has  been 
shown  to  be  one  of  the  factors  in  the  action  of  the  diuretic  salts  as 
well  as  that  of  caffeine.  As  an  unmixed  diuretic  action  it  occurs  in 
phloridzin  diabetes. 

Phloridzin  Diuresis. — Phloridzin  is  a  glucoside  but  slightly 
soluble  in  cold  water,  readily  soluble  in  alkalies  and  in  alcohol,  that 
occurs  in  the  roots  of  apple,  cherry,  and  plum  trees,  v.  Mering  dis- 
covered that  internal  administration  and,  even  better,  the  subcu- 
taneous injection  of  small  amounts  of  phloridzin,  caused  a  pro- 
nounced glycosuria,  which,  as  has  been  shown  by  later  experiments, 
is  due  to  the  formation  and  excretion  of  glucose  in  the  kidney.  The 
sugar  after  being  excreted  into  the  tubules  hinders  the  reabsorption 
of  water  by  its  osmotic  power, — that  is  to  say,  by  its  power  of  attract- 
ing and  holding  water  (Loewi,  Loewi  u.  Neubauer}. 

If  the  kidney  be  diseased,  the  glycosuria  occurs  more  tardily  and 
weakly  or  not  at  all.  This  has  led  to  an  attempt  to  use  the  glycosuria 
reaction  to  this  drug  for  the  functional  diagnosis  of  the  kidney  (Kap- 
sammer).  The  dose  administered  hypodermically  in  such  cases  is 
0.01  gm.  in  alkaline  or  dilute  alcoholic  solution. 

In  diabetes  insipidus  the  indication  is  to  limit  the  excretion  of 
urine,  some  cases  excreting  very  large  quantities  (up  to  10  1.  or  more) 
of  very  dilute  urine,  which  causes  a  constant  thirst  and  forces  the 
patient  to  consume  correspondingly  large  quantities  of  water.  The 
cause  of  this  disease  in  many  cases  is  a  disturbance  in  the  central 
nervous  system,  presumably  a  chronic  excitation  of  the  vasodilator  ; 
nerves.  In  accordance  with  such  assumption,  large  doses  of  narcotics,  i 
opiates,  valerian,  etc.,  at  times  favorably  influence  the  condition,  at 
least  temporarily.  [Strychnine  is  also  apparently  at  times  of  value  in 
the  treatment  of  this  condition.  It  is  possible  that  the  good  results 
following  its  administration  may  be  due  to  a  centrally  excited  constric- 
tion of  the  renal  vessels. — TR.] 

BIBLIOGRAPHY 

Frey:   Pfliiger's  Arch.,   1906,  vol.   112. 

Kapsammer:  Nierendiagnostik,  1907,  p.  87,  here  lit. 

Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  50. 

Loewi  u.  Neubauer:  Arch.  f.  exp.  Path.  u.  Pharm..,  1908,  vol.  59. 

v.  Mering:  Verb.  d.  Kongr.  f.  inn.  Med.,  1886. 

INFLUENCE   OF   GENERAL  AND   RENAL   METABOLISM  ON  THE    COM- 
POSITION OF  THE  URINE 

It  is  evident  that  the  chemical  composition  of  the  urine  will 
depend  on  the  metabolic  processes,  on  the  diet,  and  also  on  foreign 


URINARY  ANTISEPTICS  367 

substances,  taken  intentionally  or  otherwise,  which,  are  excreted  in 
the  urine  in  altered  or  unaltered  form  or  combination.  Ever  since 
the  investigations  of  Schmiedeberg  dealing  with  the  formation  of 
hippuric  acid  in  the  kidney,  it  has  been  known  that  the  kidney  itself 
is  capable  of  both  synthetic  and  catabolic  activity  and  in  such  fashion 
plays  a  role  in  determining  the  composition  of  the  urine. 

URINARY  ANTISEPTICS 

The  power  which  the  renal  parenchyma  possesses  of  splitting  up 
substances  into  simpler  components  is  possibly  of  much  significance 
for  the  action  of  some  of  the  urinary  antiseptics.  These  are  sub- 
stances which,  when  introduced  into  the  body,  become  active  chiefly 
or  only  after  being  split  up  in  the  kidney.  In  this  group  belong, 
among  others,  uva  ursi,  which  is  used  as  an  infusion  or  fluid  extract 
in  the  treatment  of  cystitis.  It  contains,  in  addition  to  some  tannin, 
the  glucoside  arbutin,  which  is  split  up  in  the  kidney  into  sugar  and 
the  antiseptic  hydrochinone  (seep.  514).  Salol,  much  used  as  a  urinary 
antiseptic,  may  possibly  owe  its  activity  to  a  similar  decomposition, 
and  possibly  the  same  is  true  of  the  ethereal  oils  of  copaiba,  sandal- 
wood,  and  cubebs.  In  the  metabolism  these  are  combined  with  acids, 
with  the  formation  of  the  inactive  ethereal  sulphates  and  glycuronates, 
which  possibly  are  again  changed  into  the  active  form  by  decompo- 
sition taking  place  in  the  kidney.  According  to  Jordan,  the  .oil  of 
sandal-wood  exerts  a  powerful  effect,  particularly  in  staphylococcus 
infections. 

FORMALDEHYDE  DERIVATIVES. — However,  all  the  urinary  antiseptics, 
thus  far  mentioned  are  far  less  effective  than  hexamethylenamine 
(urotropine)  and  some  closely  related  substances,  such  as  helmatose 
or  new  urotropine,  which  is  hydromethylencitrate  of  urotropine,  and 
hippol,  which  is  methylenhippuric  acid,  and  others.  The  activity  of 
these  substances  depends  on  the  fact  that  formaldehyde  is  split  off 
from  them  (Jordan). 

Hexamethylenamine, — The  decomposition  of  hexamethylenamine 
occurs  but  slowly  under  the  influence  of  a  neutral  reaction,  much  more 
rapidly  in  an  acid  medium,  and  not  at  all  in  an  alkaline  one.  Its  effi- 
ciency is  therefore  lessened  by  the  simultaneous  administration  of  alka- 
lies, and  favored  when  acids,  such  as  acid  phosphates,  are  administered. 
The  urine  in  cystitis,  as  a  rule,  does  not  become  alkaline  until  it  is  de- 
composed by  bacteria  in  the  bladder,  and  is  usually  acid  when  it  leaves 
the  kidney,  so  that  there  formaldehyde  can  be  formed  from  the  hexa- 
methylenamine. Hippol,  on  the  other  hand,  is  more  readily  decom- 
posed in  the  presence  of  an  alkaline  reaction.  These  preparations, 
hexamethylenamine  or  hippol,  in  a  dosage  of  0.5-1.0  gm.,  4-6  i.  d.,  will 
prevent  with  reasonable  certainty,  ammoniacal  fermentation  and  the 
formation  of  phosphatic  concretions  occasioned  by  it.  Other  urinary 


368  PHARMACOLOGY  OF  RENAL  FUNCTION 

infections  are  affected  by  them  in  varying  degree  according  to  the 
resistance  of  the  infecting  organisms.  The  typhoid  bacilli  seem  to  be 
more  readily  overcome  than  any  others  (R.  Stern). 

BIBLIOGRAPHY 

Jordan,  A.:  The  Action  of  Urinary  Antisept.,  Biochem.  Journ.,  1910,  vol.  5,  p.  274, 

here*  literature. 
Stern,  R.:  Z.  f.  Hygiene  u.  Infektionskr.,  1908,  vol.  59,  p.  129. 

ALKALIZATION  OF  URINE. — Acid  urine  may  be  readily  rendered 
alkaline  by  the  administration  of  alkaline  salts  or  the  salts  of  the 
vegetable  acids,  or  simply  by  a  diet  consisting  chiefly  of  vegetables 
and  fruits.  By  such  measures  it  is  possible  to  cause  an  excretion  of 
the  alkaline  carbonates  in  the  urine  which  will  neutralize  the  acids 
normally  present.  Such  measures,  as  a  rule,  increase  the  ion  concen- 
tration of  the  urine.  In  case  it  is  wished  that  the  urine  be  rendered 
alkaline  without  at  the  same  time  becoming  more  concentrated,  such 
alkalies  as  magnesia,  calcium  carbonate,  etc.,  should  be  administered. 
These  are  not  absorbed,  but  neutralize  the  acids  in  the  intestine  and 
deprive  the  urine  of  a  portion  of  its  acid  constituents.  Such  effects 
appear  to  be  of  value  when  the  indication  is  to  bring  about  the  solu- 
tion of  uratic  concretions  in  the  kidney  and  bladder.  The  recognized 
value  of  the  waters  containing  the  alkaline  earths  in  the  treatment  of 
the  uric  acid  diathesis  depends  on  such  action. 

Atophan. — The  excretion  of  uric  acid  by  the  kidney  is  not  appre- 
ciably affected  by  alkalies,  but  phenylchinolincarbonic  acid,  CieH^NO.,, 
atophan,  in  doses  of  2  to  3  gm.  daily,  very  markedly  increases  the 
excretion  of  this  substance  in  a  way  which  is  not  yet  understood.  As 
a  result  of  the  increased  removal  of  the  urates  from  the  blood,  the 
deposits  of  the  urates  in  the  joints  and  elsewhere  pass  into  solution, 
and  the  symptoms  due  to  them  are  relieved.  ( Weintraud,  also  consult 
p.  421.) 

BIBLIOGRAPHY 
Weintraud:  Ther.  d.  Gegenw.,  1911,  p.  97. 


CHAPTER  XI 

PHARMACOLOGY  OF  THE  SECRETION  OF  SWEAT 

PHYSIOLOGY 

Composition. — The  sweat,  containing  from  97.5  to  99.5  per  cent, 
of  water,  contains  less  solid  matter  than  any  other  secretion  of  the 
body  (Harnack).  Excluding  foreign  admixtures  from  the  sebaceous 
glands,  almost  three-quarters  of  its  solids,  which  amount  to  0.5-2.5 
per  cent.,  are  inorganic  salts,  chiefly  NaCl,  only  traces  of  phosphates 
and  sulphates  being  present  (Kast).  Urea  makes  up  more  than  one- 
half  of  the  organic  constituents,  which  otherwise  consist  of  urates, 
creatin,  aromatic  acids,  ethereal  sulphates,  and  other  nitrogenous 
metabolic  products  which  are  excreted  in  the  sweat. 

Under  average  conditions  of  intake  and  output  of  water,  amount- 
ing to  about  3  litres  per  diem,  the  loss  by  sweating  amounts  to  about 
40  c.c.  per  kilo  of  body  weight  every  hour,  which  for  24  hours  amounts 
to  about  700  c.c.  for  an  average  weight  of  70  kilos  (Schwenkenbecher) . 
These  figures  hold,  however,  only  during  rest  and  with  moderate  exter- 
nal temperatures,  for  under  other  by  no  means  unusual  conditions 
the  loss  of  water  through  the  skin  may  be  greatly  increased. 

Cramer  estimates,  from  the  amounts  of  sodium  chloride  on  the  surface  of 
the  skin,  814  c.c.  during  exercise  out  of  doors,  and  3208  c.c.  for  24  hours  during 
marching  in  summer  heat.  Sweat  baths  and  similar  procedures  cause  much 
more  rapid  sweat  secretion,  for  example,  %-l  litre  in  a  half  hour  (Strauss), 
but  this  naturally  only  for  comparatively  short  periods.  The  enormous  number 
of  the  sweat-glands  in  some  situations,  500-1900  to  each  square  centimetre  of 
skin,  explains  their  great  efficiency. 

9  the  estimation  of  the  NaCl  on  the  surface  of  the  skin  has  shown  that 
,t  secretion  in  man  continues  under  all  external  conditions  of  temperature 
'ramer),  although  only  in  almost  imperceptible  amounts  during  cold  weather, 
it  is  improbable  that  water  vapor  passes  through  the  epidermis  as  a  result  of 
purely  physical  processes  and  without  the  aid  of  the  sweat-glands  (Schwenken- 
becher ) . 

EXCRETION  OF  NITROGEN  AND  SALTS. — In  spite  of  their  low  concen- 
tration in  the  sweat,  the  absolute  amounts  of  urea  and  salts  thus 
lost  by  the  body  are  not  to  be  disregarded,  even  under  normal  con- 
ditions, Cramer  finding  3.7  gm.  NaCl  and  up  to  1.0  gm.  N  excreted 
by  the  skin  in  24  hours  under  conditions  of  moderate  exercise  in  the 
summer,  while  during  hard  work  in  high  temperatures  the  sweat 
secreted  may  contain  as  much  as  12  per  cent,  of  the  total  N  excreted. 
With  patients  at  rest  and  with  mean  external  temperatures  0.3  gm. 
NaCl  and  about  the  same  amount  of  nitrogen  represent  average  fig- 
ures, which  are  increased  by  thorough  sweating  up  to  1.0  gm.  of  each 
in  24  hours  (Schwenkenbecher  u.  Spetta).  The  concentration  of 
sweat  is  increased  during  active  perspiration,  but  when  this  becomes 
24  369 


370         PHARMACOLOGY  OF  SECRETION  OF  SWEAT 

really  profuse  the  concentration  falls  below  normal.  Still,  with 
impaired  renal  secretion  (anuria  in  cholera,  uraemia,  etc.)  salts  and 
urea  may  be  excreted  in  the  sweat  in  such  quantities  that  crystals  of 
NaCl  or  clusters  of  urea  crystals  have  actually  been  found  on  the  skin. 

Human  sweat  is  usually  acid  in  its  reaction,  the  acidity  being  probably  due 
entirely  to  the  fatty  acids  from  the  sebaceous  glands,  but  when  sweating  is  arti- 
ficially stimulated  it  quickly  becomes  alkaline  like  that  of  the  lower  animals 
(Triimpy,  Camerer) . 

The  sweat-glands  therefore  are  to  be  considered  as  excretory  organs 
for  water  and  salts  and  also  for  nitrogenous  metabolic  products. 
Under  normal  conditions,  however,  their  chief  function  is  that  of 
regulating  the  body  temperature,  by  providing  for  the  excretion  and 
evaporation  of  water  on  its  surface  (see  Pharmacology  of  Heat  Regu- 
lation). 

These  glands  are  very  differently  developed  in  different  animals  and  also 
in  different  parts  of  the  body.  In  man  the  whole  skin  perspires,  certain  portions 
of  the  face,  the  palms  of  the  hand,  and  the  soles  of  the  feet  being  especially 
richly  supplied  with  sweat-glands ;  but  in  cats  and  dogs  visible  perspiration  occurs 
only  in  the  hairless  soles  of  the  feet,  although  sweat-glands  do  exist  in  other 
portions  of  the  skin.  Eats,  mice,  and  rabbits  do  not  sweat  at  all,  while  it  is 
well  known  that  horses  sweat  over  the  entire  skin. 

The  secretion  of  sweat  is  a  true  glandular  activity, — that  is,  it, 
unlike  that  of  urine,  results  from  excitation  of  secretory  nerves  and  is 
relatively  independent  of  the  blood-pressure  and  blood  flow,  active 
sweating  occurring  often  in  conditions  in  which  the  skin  is  very  poorly 
supplied  with  blood  (cold  sweat,  death  sweat,  etc.),  although,  gener- 
ally speaking,  the  secretion  is  freer  when  the  blood  supply  is  ample. 

Luchsinger,  by  showing  that  stimulation  of  the  sciatic  excited  free  sweat 
secretion  after  ligature  of  an  artery  or  constriction  of  a  limb,  or  even  20  minutes 
after  amputation,  clearly  demonstrated  that  this  secretion  is  independent  of  the 
blood  supply  (Kendall,  M.  Levy). 

Innervation. — The  secretory  nerves  of  the  sweat-glands  belong  ex- 
clusively to  the  sympathetic  nervous  system  (Langley). 

Those  for  the  hind  legs  of  the  cat  leave  the  cord  partly  with  the 
twelfth  and  thirteenth  dorsal,  but  chiefly  with  the  first  and  second 
lumbar  nerves,  while  those  for  the  forelegs  pass  out  with  the  fourth 
to  ninth  dorsal  nerves.  They  all  pass  through  the  sympathetic  trunk 
and  via  the  sciatic  nerve  and  the  brachial  plexuses  respectively  to  the 
balls  of  the  feet.  The  spinal  centres  consequently  no  longer  control 
sweat  secretion  in  the  hind  legs  after  section  of  the  sciatic  or  of  the 
sympathetic  trunk  above  the  sixth  lumbar  ganglion. 

The  spinal  sweat  centres  are  primarily  under  the  control  of  the 
thermoregulatory  centres  in  the  midbrain,  but  may  also  be  influenced 
by  other  parts  of  the  central  nervous  system,  and  may  be  stimulated 
by  most  various  sensory  stimuli,  which  often  produce  sweating  only  in 


PHYSIOLOGY  371 

certain  limited  portions,  as,  for  example,  the  localized  sweating  above 
constantly  active  muscles.  The  sweating  during  nausea  and  that  due 
to  stimulation  of  the  cerebral  cortex  from  anxiety  or  fear  are  well- 
known  examples  of  the  effect  of  the  stimulation  of  the  sweat  centres 
associated  with  stimulation  of  higher  portions  of  the  central  nervous 
system  (Winkler}. 

Heat  is  the  most  important  physiological  stimulus  for  this  excre- 
tion, it  exciting  these  centres  through  the  mediation  of  higher  centres 
which  control  the  regulation  of  the  body  temperature  (see  this  chap- 
ter) and  send  impulses  down  to  them.  Kahn  has  shown  that  warming 
the  blood  flowing  to  the  head  without  warming  the  rest  of  the  body 
brings  about  a  dilatation  of  the  cutaneous  vessels  and  strongly  excites 
the  secretion  of  sweat,  thus  demonstrating  that  the  mechanism  for 
loss  of  heat  by  sweating  is  started  working  by  the  action  of  the  higher 
centres  on  centres  in  the  cord. 

Sweating  is  excited  both  by  interference  with  heat  loss  and  by 
increase  of  heat  production — for  example,  by  active  muscular  exer- 
tion— and  also  by  external  heat.  In  the  usually  employed  sweating 
procedures  the  attempt  is  made  both  to  prevent  heat  loss,  by  such 
measures  as  warm  covering  and  packs,  and  to  introduce  heat  from 
without,  as  by  drinking  hot  fluids,  such  as  tea  or  other  warm  drinks. 

Sweating  is  also  favored  by  heat  applied  locally  to  the  secretory 
nerve-endings,  for  these  respond  to  stimulation  more  actively  if  the 
skin  be  warm  than  when  it  is  cold  (Schierbeck}  •  in  fact,  cooling  of 
an  extremity  can  entirely  prevent  any  response  to  stimulation  (Ken- 
dall, Langley}. 

BIBLIOGEAPHY 


erer:  Ztschr.  f.  Biol.,  1900,  vol.  41. 
,mer:  Arch.  f.  Hyg.,  1890,  vol.  10. 
Harnack:   Fortschr.  d.  Med.,  1903,  vol.  11. 
Kahn:  Engelmann's  Arch.,  1904,  Suppl.,  p.  130. 
Kast:   Ztschr.  f.  physiol.  Chemie,  1887,  vol.  11. 
Kendall  u.  Luchsinger:  Pfluger's  Arch.,  1876,  vol.  13. 
Langley:   Journ.  of  Physiol.,  1891,  vol.  12,  p.  347. 
Langley:  Journ.  of  Physiol.,  1895,  vol.  17,  p.  296. 
Levy:   Ztschr.  f.  klin.  Med.,  1892  ,vol.  21. 
Schierbeck:  Dubois'  Arch.,  1893,  p.  116. 
Schwenkenbecher :   Arch.  f.  klin.  Med.,  1903,  vol.  79. 
Schwenkenbecher :  Verb.,  d.  Kongr.  f.  inn.  Med.,  1908. 
Schwenkenbecher  u.  Spitta:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  51. 
Strauss:  Deut.  med.  Woch.,  1904,  No.  30. 
Triimpy  u.  Luchsinger:   Pfliiger's-Arch.,  1878,  vol.  18. 
Winkler:  Pfluger's  Arch.,  1908,  vol.  125,  p.  584. 

DIAPHORETIC  DRUGS 

If  in  fever  the  cutaneous  vessels  are  contracted,  the  attempt  is 
often  made  to  overcome  this  by  alcohol,  which  is  administered  in  the 
form  of  hot  diluted  alcoholic  drinks,  with  the  object  of  dilating  the 
cutaneous  vessels  in  order  that  an  ample  blood  flow  in  the  skin  may 
favor  a  free  perspiration. 


372         PHARMACOLOGY  OF  SECRETION  OF  SWEAT 

DRUGS  ACTING  CENTRALLY 

The  secretion  of  sweat  may  also  be  excited  by  drugs  acting  on  the 
sweat  centres  as  well  as  by  those  acting  in  the  periphery.  As  any- 
thing which  stimulates  the  spinal  centres  also  stimulates  the  sweat 
centres,  strychnine,  camphor,  picrotoxine,  and  ammonium  salts  excite 
sweat  secretion  in  cats,  but  this  effect  is  not  produced  after  division 
of  the  sciatics  (Luchsinger,  Marme,  Nawrotzi).  Camphor  and  the 
liquor  ammonii  acetatis  were  formerly  much  used  as  sudorifics. 

BIBLIOGRAPHY 

Luchsinger:  Pfliiger's  Arch.,  1876,  vol.  17,  p.  369. 
Luchsinger:   Pfliiger's  Arch.,  1878,  vol.  16,  p.  510. 
Marine":   Nachr.  d.  Gott.  Ges.  d.  Wiss.,  1878. 
Nawrotzki:  Zbl.  f.  med.  Wiss.,  1878,  1879. 

DRUGS  ACTING  ON  THE  PERIPHERY 

The  sympathetic  nerve-endings  in  the  glands  are  acted  upon  by  a 
number  of  drugs  which  elsewhere  act  only  on  autonomic  nerve-endings, 
while  epinephrin,  which  elsewhere  acts  specifically  on  the  sympathetic 
system,  has  no  effect  on  the  sweat-glands,  in  contradistinction  to  its 
effect  on  the  glands  in  the  skin  of  the  frog.  On  the  other  hand,  mus- 
carine,  pilocarpine,  and  physostigmine  all  excite,  while  atropine  sup- 
presses, the  secretion  of  sweat.  Although  the  innervation  of  the 
sweat-gland  is,  as  far  as  is  known,  purely  sympathetic,  in  their  phar- 
macological reactions,  their  insusceptibility  to  epinephrin  and  their 
susceptibility  to  the  autonomic  drugs,  they  behave  entirely  like  organs 
with  autonomic  innervation.  No  explanation  has  thus  far  been  found 
for  this  striking  exception  to  otherwise  apparently  general  laws. 

Luchsinger  long  ago  demonstrated  that  muscarine,  pilocarpine,  physostig- 
mine, and  atropine  act  peripherally  in  the  sweat-glands.  Pilocarpine  especially 
has  a  strong  sudorific  effect  in  the  cat's  paw,  even  after  section  of  the  sciatic; 
in  fact,  at  first  it  acts  more  strongly  on  the  side  where  the  nerve  has  been  cut 
than  on  the  other  side,  and  the  same  is  true  of  muscarine  ( Triimpy ) ,  but,  accord- 
ing to  Luchsinger,  the  intravenous  injection  of  physostigmine  produces  no  effects 
on  the  sweat-glands  after  they  have  been  cut  off  from  their  nervous  centres. 
Under  these  conditions  it  excites  secretion  only  when  injected  under  the  skin  of 
the  paw.  These  observations  are  in  no  way  surprising  in  view  of  the  pharmaco- 
logical characteristics  of  this  drug  (see  p.  148),  for,  while  everywhere  markedly 
increasing  the  excitability  of  nerve-endings,  it,  in  contradistinction  to  muscarine 
and  pilocarpine,  does  not  itself  act  as  a  direct  stimulus. 

It  is  entirely  in  agreement  with  the  fact  that  these  drugs  act 
peripherally  that  after  an  injection  of  pilocarpine  the  general  sweat- 
ing is  preceded  by  a  strictly  localized  perspiration  (Cloetta),  which 
after  very  small  doses  may  be  all  that  occurs  (Strauss),  and  that,  on 
the  other  hand,  small  doses  of  atropine  given  hypodermically  may 
produce  only  a  local  suppression  of  perspiration. 

Arecoline,  the  alkaloid  of  the  areca  nut,  and  nigelline,  from  the  seeds  of 
Nigella  sativa  (Pellacani),  act  like  pilocarpine,  but  are  of  no  practical  signifi- 
cance. 


DIAPHORETIC  DRUGS  373 

In  the  sweat-glands,  as  in  the  salivary  glands,  pilocarpine  and 
atropine  are  reciprocally  antagonistic;  but  the  affinity  between  atro- 
pine  and  the  nerve-endings  is  so  much  the  stronger,  that  pilocarpine 
can  start  up  the  sweat  secretions  again  only  in  case  the  dose  of 
atropine  has  not  been  too  large,  while  atropine  is  able  to  counteract 
even  the  strongest  pilocarpine  action  (Luchsinger}. 

The  action  of  nicotine  on  the  secretory  nerves  of  the  sweat-glands  accords 
fully  with  other  experiences  bearing  on  the  action  of  this  drug  on  the  relay 
stations  (ganglia)  in  the  vegetative  nervous  system.  Luchsinger  found  that 
after  section  of  the  sciatic  it  was  either  not  at  all  or  only  very  slightly  active. 
According  to  Langley,  the  ganglia  of  the  sudoriparous  fibres  lie  in  the  sympathetic 
trunk,  which  arrangement  accords  with  the  fact  that  the  primarily  exciting 
action  of  nicotine  is  localized  at  this  point. 

Central  Actions  of  These  Drugs. — Pilocarpine,  physostigmine,  and  nicotine 
also  stimulate  the  spinal  sweat  centres,  as  shown  by  Luchsinger,  who  found  these 
drugs,  when  injected  into  the  back,  produced  sweating  in  the  extremities  even 
after  the  arteries  supplying  them  had  been  ligated.  This  central  action  of  these 
drugs  is  to  be  considered  as  analogous  to  that  of  other  central  excitants,  such  as 
camphor,  picrotoxin,  and  many  others,  for  all  three  at  first  cause  an  excitation 
of  the  cord,  which  manifests  itself  by  dyspnoea  and  after  toxic  doses  by  convul- 
sions, and  which  after  pilocarpine  is  especially  lasting  but  with  nicotine  soon 
passes  over  into  paralysis  (Harnack  u.  H.  Meyer).  It  is  readily  comprehensible 
that  augmentation  of  the  impulses  from  the  centres  will  be  especially  effective 
in  combination  with  the  simultaneous  excitation  of  the  terminal  nervous  organs. 
This  is  especially  so  with  physostigmine,  whose  peripheral  action  is  solely  to 
increase  the  excitability  of  the  terminal  nervous  organs. 

In  therapeutics  of  the  substances  mentioned  only  pilocarpine  is  of 
importance  as  a  diaphoretic  or  hidrotic,  while  atropine  is  the  most 
important  antihidrotic. 

PILOCARPINE  is  derived  from  the  jaborandi  leaves  obtained  from 
different  pilocarpus  plants,  and  is  accompanied  in  the  leaves  of 
Pilocarpus  jaborandi  by  a  second  alkaloid  with  similar  but  very  much 
weaker  actions  (Harnack).  The  leaves  were  introduced  from  Brazil 
in  the  seventies,  but  they  have  been  found  to  be  unreliable  and  uncer- 
tain in  their  actions,  perhaps  on  account  of  the  presence  in  them  of 
jaborin,  a  decomposition  product  of  pilocarpine  of  basic  nature  and 
atropine-like  action,  which  may  also  be  present  in  impure  pilocarpine. 
The  use  of  the  leaves  has  therefore  been  abandoned,  and  properly  so. 

The  hydrochlorate  of  pilocarpine  is  the  preparation  to  be  used, 
and  it  is  usually  administered  hypodermically  in  doses  of  0.005-0.01 
gin.  (maximum,  for  single  dose  0.02  gm.  ( ! !  TR.)  ,  per  diem  0.04  gm.) 

Usually  ten  or  fifteen  minutes  after  an  injection  the  skin  becomes 
reddened  and  very  profuse  sweating  occurs,  lasting  about  two  hours, 
during  which  time  as  much  as  2  kilos  of  fluid  may  be  secreted.  An 
increase  of  salivary  secretion  almost  always  accompanies  or  precedes 
the  sweating  and  persists  somewhat  longer.  The  salivary  secretion 
usually  is  not  increased  to  a  disturbing  extent,  but  occasionally  the 
effect  on  the  salivary  glands  exceeds  that  on  the  sweat-glands  or  it 
alone  may  occur.  The  secretions  of  all  other  true  glands  are  also 
increased,  among  them  those  of  the  lachrymal,  bronchial,  and  tracheal 


374         PHARMACOLOGY  OF  SECRETION  OF  SWEAT 

glands.  The  effect  on  the  bronchial  glands  is  of  practical  importance, 
inasmuch  as  it  may  increase  the  danger  of  oedema  of  the  lungs  in 
individuals  already  predisposed  thereto.  This  drug  produces  no  de- 
monstrable effects  on  the  renal  or  lacteal  secretions. 

OTHER  ACTIONS. — "While  an  increase  in  the  various  secretions  may 
be  induced  by  muscarine  or  nicotine  only  simultaneously  with  other 
dangerous  symptoms,  after  pilocarpine  this  is  usually  the  first  effect 
produced,  and  occurs  after  such  small  doses  that  there  is  no  danger 
to  be  apprehended  from  its  actions  on  the  various  autonomic  nerve- 
endings.  In  its  actions  on  these  it  closely  resembles  muscarine  and 
nicotine.  Its  effects  on  the  eye  (p.  153) ,  on  the  intestine  (p.  190) ,  and  on 
the  uterus  (p.  222)'  are  analogous  to  those  of  muscarine,  while  its  action 
on  the  heart  is  identical  with  that  of  nicotine.  These  side  actions  are 
often  disagreeable  and  disturbing  when  pilocarpine  is  administered 
medicinally.  Especially  visual  disturbances  and  nausea  and  vomiting 
may  result  from  its  administration,  but  colic  and  diarrhoea  occur 
only  rarely.  As  even  therapeutic  doses  excite  uterine  contractions, 
this  drug  should  not  be  administered  to  pregnant  women  [except 
in  the  presence  of  the  clearest  indications. — TR.  ] . 

At  the  start  pilocarpine  produces  excitation  of  the  central  nervous 
system.  In  animal  experiments  the  paralysis  of  the  vasomotor  and 
respiratory  centres  results  only  from  much  larger  doses  than  those 
which  cause  an  increased  secretion  of  sweat.  Still  the  collapse  which 
not  infrequently  has  been  observed  in  man,  when  larger  doses  of  pilo- 
carpine have  been  given,  may  be  a  result  of  this  central  paralysis. 
It  is  therefore  contraindicated  to  use  pilocarpine  in  doses  larger 
than  0.01  gm. ! 

According  to  Eichelberg,  pilocarpine  causes  an  increase  in  metabolism  during 
the  active  glandular  activity  caused  by  it.  In  the  fasting  animal  the  increase 
of  the  C02  excretion  during  the  period  of  secretion  amounts  to  only  about 
9  per  cent.  (Frank  u.  Voit).  It  is  therefore  not  very  marked,  but  may  well  be 
of  some  importance  in  causing  the  wasting  which  may  occur  when  sweating 
cures  are  employed  (Schwenkenbecher  u.  Inagaki). 

OTHER  DIAPHORETICS. — In  addition  to  pilocarpine,  only  the  sali- 
cylates  and  other  antipyretics  are  of  much  importance  as  diaphoretics. 
These  produce  their  diaphoretic  action  by  their  effect  on  the  regu- 
lation of  the  body  temperature,  by  acting  on  those  higher  centres 
which  control  the  spinal  sweat  centres  (see  p.  370) . 

BIBLIOGRAPHY 

Cloetta,  cited  by  Luchsinger:  Pfluger's  Arch.,  1876,  vol.  15. 

Eichelberg:  Inaug.-Diss.,  Marburg,  1903. 

Frank  u.  Voit:  Ztschr.  f.  Biol.,  1903,  vol.  44,  p.  111. 

Harnack:  Arch.  f.  exp.  Path.  u.  Pharm.,  1886,  vol.  20,  p.  439. 

Harnack  u.  Hans  Meyer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1880,  vol.  12,  p.  296. 

Langley:  Journ.  of  Physiol.,  1891,  vol.  12,  p.  347. 

Langley:  Journ.  of  Physiol.,  1895,  vol.  17,  p.  296. 

Luchsinger:   Pfluger's  Arch.,  1876,  1877,  1878. 

Marshall :  Journ.  of  Physiol.,  1904,  vol.  31,  p.  120. 


DIAPHORETIC  DRUGS  375 

Pellacani:  Arch.  f.  exp.  Path.  u.  Pharm.,  1883,  vol.  16,  p.  440. 
Schwenkenbecher  u.  Inagaki:   Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  55. 
Strauss:   Compt.  rend.,  Paris,  1879. 
Triimpy  u.  Luchsinger:  Pfliiger's  Arch.,  1878,  vol.  18,  p.  503. 

INDICATIONS  FOR  DIAPHORESIS 

Diaphoresis  may  be  employed  for  the  purpose  of  removing  water 
from  the  body  or  to  bring  about  an  excretion  through  the  skin  of 
substances  ordinarily  excreted  by  the  kidney.  In  addition  to  these 
scientifically  well-grounded  indications,  diaphoresis  is  frequently  em- 
ployed empirically  to  meet  various  others, — as,  for  example,  in  the 
beginning  of  infectious  diseases,  with  the  idea  of  securing  the  elimina- 
tion of  bacterial  toxins,  or  in  a  number  of  mild  febrile  affections, 
such  as  bronchitis,  etc.,  to  "bring  them  to  the  surface."  It  is  prob- 
able that  the  experience,  that  in  many  infectious  diseases  improve- 
ment often  starts  simultaneously  with  the  appearance  of  profuse 
sweating,  has  led  to  the  belief  that  the  improvement  in  the  patients  is 
due  to  this. 

IN  RENAL  DISEASE. — On  the  other  hand,  the  excitation  of  profuse 
diaphoresis  is  of  proven  value  in  acute  or  chronic  renal  insufficiency, 
as  the  vicarious  secretion  through  the  skin,  which  in  the  course  of 
a  thorough  sweating  may  remove  large  amounts  of  water,  urea,  NaCl, 
etc.,  from  the  body,  helps  to  relieve  the  kidney. 

It  is  no  unusual  clinical  experience  to  see,  in  cases  with  insufficient 
or  suppressed  renal  secretion  and  impending  uraemia,  an  improved 
diuresis  follow  a  thorough  sweating,  and  this,  too,  independently  of  the 
mechanical  relief  secured, — such,  for  example,  as  relief  of  the  com- 
pression of  the  renal  veins  by  ascites.  This  reminds  one  of  the  fact 
mentioned  on  page  356,  that  an  excess  of  salts  in  the  blood  may  cause 
a  lessening  of  the  renal  secretion,  which  may  be  relieved  by  with- 
drawing salt  from  the  diet.  The  removal  of  salt  from  the  body  by 
sweating  may  have  a  similar  favorable  effect. 

Sweating  may  also  be  employed  as  a  measure  of  last  resort  to 
remove  fluid  in  dropsical  conditions,  but  in  connection  with  the  use 
of  pilocarpine  in  cardiac  patients  it  is  important  to  remember  that 
this  drug  may  cause  collapse. 

The  effects  produced  by  pilocarpine  when  employed  as  an  "absorb- 
ant,"  for  the  purpose  of  aiding  in  the  absorption  of  exudates  or  of 
extravasations  of  blood  in  the  anterior  chamber  of  the  eye  or  of  cloudi- 
ness in  the  vitreous  humor,  probably  depend  on  the  temporarily 
increased  concentration  of  the  blood  which  may  result  from  sweating, 
even  when  the  water  content  of  the  tissues  is  so  low  that  diuretics 
fail  to  act. 

SUPPRESSION  OF  THE  SECRETION  OF  SWEAT 
ATROPINE  in  doses  of  0.5-1.0  nag.,  usually  given  hypodermically 
[?TR.],  may  be  employed  with  advantage  for  the  purpose  of  sup- 
pressing profuse  sweating,  such  as  the  "night-sweats"  of  consump- 


376         PHARMACOLOGY  OF  SECRETION  OF  SWEAT 

tives.  As  the  very  first  expression  of  the  action  of  atropine  is  the 
inhibition  of  various  glandular  secretions,  such  doses  may  accomplish 
this  without  necessarily  causing  any  other  atropine  effects  except 
some  dryness  of  the  mouth  and  throat,  but  if  the  dose  be  increased 
or  often  repeated  the  other  atropine  effects  may  prove  very  disturbing. 

Agaricin. — Agaricinic  acid,  which  is  obtained  from  the  white  agaric 
(Polyporus  officinalis ) ,  long  known  to  possess  antihidrotic  properties,  acts  on 
the  secretory  nerve-endings  like  atrophine.  This  is  the  active  substance  contained 
in  the  impure  commercial  preparation  known  as  agaricin,  which  is  often  used  in 
the  treatment  of  the  night  sweats  of  phthisis  (0.005-0.01  gm.  for  single  doses, 
0.1  gm.  maximum  dose  for  24  hours).  It  has  been  shown  by  Hofmeister  that  this 
substance,  which  in  large  doses  acts  as  a  narcotic  but  which  otherwise  is  not 
pharmacologically  related  to  atropine,  exerts  a  weak,  atropine-like  action  on  the 
sweat  secretion  and  does  this  in  relatively  non-toxic  doses.  Under  its  influence 
sweating  does  not  occur  as  it  usually  does  when  a  cat's  paw  is  kept  warm.  This 
eft'ect  is  peripherally  induced,  for  after  agaricin  stimulation  of  the  sciatic  is 
ineffective.  On  account  of  its  local  irritant  action,  agaricin  cannot  be  adminis- 
tered hypodermically. 

Camphoric  acid,  obtained  by  the  oxidation  of  camphor,  in  doses 
of  1-2  gm.  is  also  employed  to  prevent  night-sweats,  but  no  experi- 
mental investigations  of  its  efficiency  have  been  made  (Vejux  Tyrode). 

Astringents,  such  as  tannic  acid  and  astringent  antiseptics,  may  be 
useful  in  relieving  local  hyperhidrosis. 

BIBLIOGRAPHY 

Hofmeister:  Arch.  f.  exp.  Path.  u.  Pharm.,  1888,  vel.  25,  p.  189. 

Vejux  Tyrode,  M.:    Arch,  intern,  de  Pharmacodynamie,  1908,  vol.  18,  p.  393. 


CHAPTER  XII 

PHARMACOLOGY  OF  THE  METABOLISM 
GENERAL  CONSIDERATIONS 

IN  the  living  body  there  is  a  constant  change  taking  place  in  the 
forces  and  substances  which  form  and  maintain  it.  The  organism 
is  able  to  maintain  itself  and  keep  its  weight  and  chemical  composition 
constant,  except  for  occasional  variations,  only  by  periodically  ab- 
sorbing and  assimilating  material  to  replace  that  constantly  lost  by 
disintegration  and  death  of  its  tissues,  for  living  matter  is  constantly 
dying.  We  speak,  therefore,  of  metabolic  balance  and  equilibrium 
and  of  positive  and  negative  metabolic  balance,  depending  on  whether 
or  not  assimilative  or  dissimilative  phenomena  are  preponderant.  All 
the  chemical  substances  constituting  the  body  take  part  in  the  tissue 
change,  the  inorganic  mineral  constituents  which  largely  constitute  the 
framework  of  the  body  taking  the  least  active  part  in  these  changes:, 
but  still  taking  some  part  therein.  Therefore  all  the  constituents  of 
the  body  must  be  constantly  replaced  to  some  extent  if  the  organism 
is  to  survive  (law  of  the  minimum).  Naturally  the  most  active 
metabolism  is  that  of  the  readily  oxidized  organic  substances,  of 
which  the  proteids,  fats,  and  carbohydrates  are  the  most  important, 
for  these,  on  account  of  their  oxidizability,  are  at  once  the  creators 
and  the  victims  of  the  chemical  energy,  which  enters  the  body  with 
them  only  to  leave  it  almost  entirely  in  the  form  of  heat  and  work. 

The  chemical  processes  of  oxidation  and  decomposition  are  in 
theory  of  two  types : 

1.  Decay  of  protoplasm  as  the  result  of  the  naturally  limited  life 
of  all  cells,  the  tissue  change  of  death  or  of  wear  and  tear,  which 
takes  place  without  regard  to  the  energy  which  thus  unavoidably 
becomes  available.     This  is  especially  apparent  in  the  decay  of  the 
epithelium  of  the  skin  and  similar  tissues  and  in  that  of  the  nuclear 
constituents,  both  of  which  are,  from  a  caloric  point  of  view,  of  minor 
significance. 

2.  Decomposition  of  the  replaceable  constituents  of  the  protoplasm 
for  the  purpose  of  supplying  the  energy  (heat  and  force)  necessary 
to  life.     This  is  functional  tissue  change,  or  metabolism  of  work, 
which  occurs  without  combustion  of  the  formed  elements.    In  general 
this  corresponds  to  the  metabolism  of  nutrition,  it  being,  in  other 
words,  the  combined  result  of  dissimilation  or  catabolic   (splitting) 
processes  and  of  assimilation  or  anabolic  (synthetic)  processes  in  the 
cells  of  the  body,  and  is  in  rapidity  and  extent  by  far  the  more  im- 
portant type  of  tissue  change. 

The  total  metabolism,   therefore,  renders  possible  the  transfor- 
,tion  of  energy  in  the  body,  which  may  be  measured  directly  by 

377 


378  PHARMACOLOGY  OF  THE  METABOLISM 

determining  the  caloric  intake  and  output  or  indirectly  by  determining 
the  consumption  of  oxygen  and  the  output  of  carbon  dioxide.  (For 
methods,  Magnus-Levy,  Durig.} 

The  amount  of  the  energy  transformed  varies  within  wide  limits, 
being  governed  by  external  and  internal  conditions  influencing  the 
organism  and  by  the  work  performed.  A  certain  minimum  is,  how- 
ever, necessary  to  maintain  the  body  temperature,  the  heart's  action, 
respiration,  etc.,  and,  if  the  functional  metabolism  cannot  supply 
this,  the  tissues  themselves  are  consumed.  A  sharp  distinction  can, 
however,  not  be  drawn  between  these  two  sources  of  supply,  for  reserve 
material  is  stored  up  in  the  different  organs,  which,  in  case  of  insuffi- 
cient nutrition,  is  rendered  available  for  oxidation,  and  in  the  fol- 
lowing order,  first  carbohydrates,  second  fats,  and  last  of  all  pro- 
teids.  Only  when  this  reserve  supply  has  been  consumed  does  a 
rapid  destruction  of  cells  begin. 

The  measurement  of  the  energy  transformed  furnishes  a  general 
gauge  for  the  momentary  tissue  change,  but  gives  no  indication  of  the 
manner  or  extent  to  which  each  of  the  three  main  food-stuffs,  proteids, 
carbohydrates,  and  fats,  take  part  in  this  process.  With  the  total 
transformation  of  energy  remaining  constant,  it  is  possible  for  these 
three  mainstays  of  metabolism  to  be  involved  in  very  different  pro- 
portions, for  they  can,  within  certain  limits,  replace  one  another  in 
accordance  with  their  caloric  values,  an  abnormally  increased  or 
diminished  decomposition  and  oxidation  of  one  constituent  of  the 
body  being  compensated  for  by  the  opposite  behavior  of  the  others. 
As  here  it  is  a  question  of  equivalent  quantities,  not  in  terms  of  mass 
but  in  those  of  caloric  values  (according  to  Eubner  in  round  figures 
100  gm.  fat  •=.  230  gm.  glycogen  =  230  gm.  dried  muscle  proteid  or 
980  gm.  lean  meat),  the  body  may  gain  or  lose  in  the  mass  of  its 
organic  constituents,  while  a  constant  amount  of  energy  is  trans- 
formed, according  as  it  retains  or  consumes  larger  amounts  of  carbo- 
hydrate or  smaller  amounts  of  fat,  which  are,  however,  calorically 
equivalent.  On  the  other  hand,  the  mass  of  material, — i.e.,  the  body 
weight — may  remain  constant  and  energy  be  lost  if,  for  example,  100 
gm.  of  fat  be  consumed  and  100  gm.  of  carbohydrate  be  assimilated. 
Determinations  of  the  energy  transformed  consequently  can  indicate 
only  the  extent  of  tissue  change,  but  cannot  show  whether  the  tissue 
balance  is  positive  or  negative.  The  much-used  expression,  "stimula- 
tion of  metabolism,"  is  therefore  in  no  sense  an  exact  one,  for  it  may 
signify — and  this  is  the  usual  meaning  in  therapeutic  literature : 

1.  AN  INCREASED  TRANSFORMATION  OF  ENERGY, — i.e.,  increased  heat 
production  and  increased  functional  activity  of  the  organs,  resulting 
in  an  increase  in  the  intensity  and  speed  of  all  the  phenomena  of  life 
and  of  decay.  In  other  words,  it  may  mean  that  in  a  given  time  more 
oxidizable  material  is  consumed  without  considering  for  the  time 
any  change  in  the  energy  balance.  If  one  assumes  with  Eubner 
that  each  and  every  cell  protoplasm  during  its  life  is  capable  of 


GENERAL  CONSIDERATIONS  379 

transforming  a  certain  amount  of  energy,  and  that,  after  performing 
a  given  amount  of  work,  it  is  used  up  and  disintegrates,  it  is  evident 
that  a  therapeutic  acceleration  of  the  transformation  of  energy  will 
bring  about  a  more  rapid  dying  off  of  cells  already  feeble  from  old  age 
or  otherwise  pathologically  weakened,  and  that  thus  the  new  growth 
of  the  healthy  younger  generation  replacing  them  may  be  accele- 
rated. In  this  fashion  purification  and  regeneration  may  be  brought 
about  and  the  useless  elements  be  removed  from  the  body.  The  utility 
of  all  those  therapeutic  agencies,  which  in  an  indirect  fashion  tend 
to  increase  the  transformation  of  energy,  probably  depends  on  their 
power  of  inducing  such  regeneration.  Among  such  measures  stimu- 
lation of  the  skin,  sea-bathing,  climate,*  sports,  and  massage  may  be 
mentioned.  In  so  far  as  they  facilitate  or  stimulate  muscular  activity, 
the  stimulants  of  the  central  nervous  system  may  be  considered  as 
doing  this.  Among  these  are  strychnine,  caffeine,  alcohol  in  small 
amounts, — in  short,  all  those  drugs  known  as  "excitantia  nervina," 
or  nerve  stimulants. 

Disappearance  of  Pathological  Tissue  as  a  Result  of .  General 
Acceleration  of  the  Transformation  of  Energy. — Such  a  regenerative 
selection — that  is,  an  extermination  of  less  resistant,  degener- 
ated, or  otherwise  weakened  body  cells — may  be  accomplished  by 
chemical  or  physical  forces,  which,  while  reaching  all  or  most  cells 
in  equal  intensity,  exert  on  them  an  action  supported  without  apparent 
damage  by  healthy  cells,  but  fatal  to  unhealthy  ones.  This  may  be 
compared  to  the  way  in  which  it  is  possible  by  the  application  of  such 
mild  caustics  as  lactie  acid  to  destroy  diseased  tissue  without  harming 
the  healthy  tissue  necessarily  submitted  to  the  same  treatment.  Of 
the  agencies  acting  in  this  fashion  the  physicochemical  ones,  heat  and 
radiant  energy,  may  be  considered  as  having  such  effects,  though  only 
to  a  limited  extent.  Variations  in  the  osmotic  tension  of  the  tissue 
cells — that  is,  in  their  water  and  their  salt  content — produce  such 
effects  to  a  marked  extent.  This  is  the  basis  for  the  various  popular 
blood-purifying  cures,  water  cures,  thirst  cures,  and  so  forth. 

Specific  Alteration  of  Metabolism. — While  an  alteration  of  osmotic 
conditions  affects  all  the  cells  of  the  body  as  a  whole,  and  by  physico- 
chemical  "mass  action"  disturbs  the  chemical  equilibrium  of  all  of 
them,  considered  as  elementary  organisms,  and  alters  their  function, 
there  are  also  purely  chemical  agents,  which  in  a  more  delicate  man- 
ner, that  is  not  susceptible  of  a  further  analysis,  accelerate  or  retard 
only  certain  of  the  chemical  reactions  of  protoplasm,  without  otherwise 
altering  its  structure  or  function.  These  may  be  looked  upon  as 
specific  catalyzers  of  the  metabolic  processes,  to  which  we  reckon  the 
products  of  certain  glands,  especially  that  of  the  thyroid  and,  in  a 
limited  and  opposite  way,  quinine. 

2.  Stimulation  of  the  metabolism  indicates  quite  another  thing 
when  the  object  is  to  secure  an  increased  assimilation  of  material, 


*  See  Loewy  u.  Fr.  Miiller. 


380  PHARMACOLOGY  OF  THE  METABOLISM 

whether  this  means  a  more  rapid  and  greater  increase  of  weight 
in  young,  rapidly  growing  individuals  or  the  attainments  of  a  better 
state  of  nutrition  in  badly  nourished  adults,  such  as  invalids  or  con- 
valescents. Here  the  indication  is  not  to  accelerate  the  transformation 
of  energy  by  increasing  catabolic  processes,  such  as  oxidation  and 
cleavage,  but  rather  to  moderate  it  as  far  as  possible  or  to  over- 
compensate  for  it.  As  a  matter  of  fact,  in  such  cases  the  transfor- 
mation of  energy  is,  as  a  rule,  augmented,  while  proteid  is  assimilated 
and  retained  as  organ  proteid.  In  addition  to  purely  dietetic  measures 
and  those  which  improve  the  appetite  and  the  digestion  and  absorp- 
tion, such  as  forced  feeding,  with  exercise,  a  number  of  pharmacologi- 
cal agents  may  produce  these  effects  by  specifically  influencing  tissue 
change  in  such  fashion  that  assimilation — that  is,  the  synthetic  for- 
mation of  new  body  substance — is  stimulated,  and  a  condition  results 
similar  to  that  of  the  youthful  growing  organism  (Hoffstrom)  or  to 
that  of  an  individual  convalescing  from  an  exhausting  disease  (Lilthje 
u.  Berger}.  Of  the  manner  in  which  such  effects  are  produced  little 
is  known  up  to  the  present. 

"Wpien  the  action  is  more  pronounced  or  when  toxic  doses  are  given, 
these  same  substances  act  harmfully  on  the  protoplasm  of  the  cells, 
causing  their  rapid  death  and  accelerating  their  disintegration.  Under 
certain  conditions  both  the  favorable  and  the  destructive  actions  may 
occur  simultaneously  in  the  body  as  a  result  of  the  variable  resisting1 
powers  of  the  cells  of  the  body.  This  may  explain  many  specific 
curative  actions. 

Furthermore,  such  actions  on  metabolism,  partly  conservative 
and  partly  harmful,  may  be  so  feeble  or  may  be  limited  to  such  small 
especially  susceptible  portions  of  the  body  that  they  cause  no  observ- 
able effects  on  the  general  metabolism  and  therefore  cannot  be  meas- 
ured. However,  clinical  observation  of  resulting  changes  in  the 
distribution  of  material  in  the  body,  such  as  the  absorption  of  exu> 
dates,  tumors,  or  connective-tissue  growths,  can  give  sufficient  evidence 
to  permit  the  assumption  of  such  actions  on  the  metabolism.  The 
substances  producing  such  results  will  be  considered  later  in  the 
group  of  inhibitors  of  oxidation  (p.  404). 

3.  Finally,   AN  ALTERATION   OF   METABOLISM   may  be   considered, 

WHICH  AFFECTS  CHIEFLY  OR  ENTIRELY  ONLY  CERTAIN  CONSTITUENTS  OB 

DECOMPOSITION  PRODUCTS  OF  THE  PROTOPLASM  of  the  body.  This  there- 
fore demands  a  special  discussion.* 

*  This  general  discussion  and  division  under  1,  2,  and  3  are  schematic  and  to 
a  certain  extent  arbitrary,  for  they  include  only  some  of  the  pharmacologically 
interesting  phases  of  metabolism. 

In  physiology  it  is  customary  to  differentiate  between  the  tissue  change  neces- 
sary for  maintenance  of  metabolism  during  rest,  i.e.,  the  energy  transformation 
occurring  in  a  fasting  human  being  during  complete  inactivity,  and  the  augmen-  i 
tation  of   metabolism  resulting  from  definite  work   performed   by  the  organs — • 
functional  metabolism.    The  metabolism  during  rest,  however,  in  addition  to  the  i 


GENERAL  CONSIDERATIONS  381 

In  so  far  as  the  function  of  the  cells  is  under  central  nervous 
control,  it  is  clear  that  their  metabolism  also  may  be  indirectly  in- 
fluenced through  the  central  nervous  system,  for  every  functional  act, 
every  cell  activity,  depends  on  a  catabolic  change,  which  is  quickly 
followed  by  a  compensating — often,  in  fact,  by  an  over-compensating 
— restorative  process.  This  reaction  resulting  in  compensation  or 
over-compensation  is  one  which  we  are  not  yet  able  to  analyze  or 
understand.  Like  the  capacity  for  growth,  it  is  an  essential  character- 
istic of  living  matter. 

The  stimulation  of  growth,  with  assimilation  of  proteid,  which  con- 
tinued and  violent  muscular  exercise  causes  is  the  best  example  of  such 
over-compensation  (Caspari,  Loewy,  Bornstein).  The  increased  blood 
and  food  supply  brought  to  the  organ  as  a  result  of  its  functional 
activity  doubtless  is  a  factor,  but  only  a  partial  factor,  in  this  result. 
On  the  other  hand,  organs  forced  to  remain  inactive  undergo  atrophy. 

The  chemical  regulation  of  the  body  temperature  (see  Chapter  XV) 
is  another  instance  of  a  metabolic  process  controlled  by  the  nervous 
system,  which  demands  special  separate  consideration. 

BIBLIOGRAPHY 

Bernstein:   Pfliiger's  Arch.,  1901,  vol.  83. 

Caspari:   Pfliiger's  Arch.,  1901,  vol.  83. 

Durig:  Ueber  den  Erhaltungsumsatz.  Akad.  d.  Wiss.  Wein.,  1909,  vol.  86,  p.  116. 

Hoffstrom:  Acad.  Abh.  der  Universitat  Helsingfors,  Leipzig,   1910. 

Loewy:   Dubois'  Arch.,   1901. 

Loewy  u.  Fr.  Miiller:   Ztschr.  f.  Balneologie,  Klimatologie,  etc.,  1910,  vol.  3,  p.  1. 

Loewy  u.  Fr.  Miiller:   Ztschr.  f.  exp.  Path.  u.  Ther.,  1909,  vol.  7. 

Liithje  u.  Berger:  Deut.  Arch.  f.  klin.  Med.,  1904,  vol.  81,  p.  278. 

Magnus-Levy:   Noorden's  Handb.  d.  Path.  d.  Stoffw.,  1906,  vol.  1,  p.  200. 

Aside  from  these  indirect  influences  through  the  central  nervous 
system,  all  physical  or  chemical  stimuli  which  act  directly  on  the  cells 
of  the  body  must  influence  their  chemical  activity,  and  thus  affect  the 
transformation  of  matter  and  energy  in  them.  For  reasons  of  prac- 
tical import,  it  is  advantageous  to  start  the  discussion  of  such  direct 
influences  with  that  of — 

purely  vegetative  metabolism  of  decay,  includes  a  large  portion  of  the  functional 
metabolism,  as  it  necessarily  includes  the  metabolism  resulting  from- the  activity 
of  the  heart,  of  the  respiratory  system,  and  of  the  glands,  as  well  as  that 
involved  in  the  production  of  heat.  These  two  components,  however,  are  in- 
fluenced by  pharmacological  agents  in  very  different  degrees  and  in  opposite 
directions.  Drugs  which,  like  arsenic,  influence  the  metabolism  of  decay,  affecting 
the  duration  of  the  life  of  the  cells,  do  not  necessarily  produce  an  appreciable 
alteration  in  the  metabolism  of  function.  On  the  other  hand,  drugs  affecting 
function,  such  as  the  narcotics,  or  those  acting  on  nerves  or  on  the»  heart,  etc., 
as  a  general  rule  do  not  affect  the  metabolism  of  decay,  although  they  primarily 
increase  or  decrease  the  transformation  of  energy  and  material,  the  functional 
metabolism,  only  of  the  organs  whose  activity  is  stimulated  or  depressed.  For 
these  reasons  the  appreciation  of  the  difference  between  metabolism  of  decay 
and  metabolism  of  function  appears  essential  to  the  proper  understanding  of  the 
manner  in  which  drugs  produce  alterations  in  the  metabolism. 


382  PHARMACOLOGY  OF  THE  METABOLISM 


i.  THE  TEMPERATURE  OF  THE  BODY 

It  is  well  known  that  an  increase  in  the  temperature  causes  an 
acceleration  of  the  rate  at  which  all  chemical  reactions  take  place. 
According  to  van't  Hoff,  a  rise  of  10°  C.  almost  doubles  or  trebles 
the  rate  of  reaction.  Within  certain  limits  of  temperature  the  same 
holds  good  for  biological  phenomena  (Linser  and  Sclimid,  Matthes, 
Kanitz),  every  rise  in  the  body  temperature  beyond  the  normal  in- 
creasing and  accelerating  the  metabolism,  while  marked  lowering  of 
the  body  temperature  retards  and  lessens  the  metabolism  (Rumpff). 

Such  overheating  or  cooling  of  the  body  may  indirectly  result  from  the 
action  of  drugs  which,  like  cocaine,  tetrahydronaphthylamine,  and  atropine,  excite 
the  centres  controlling  the  he?.t  regulation,  or  which,  like  the  narcotics,  especially 
alcohol  and  chloral  and  the  antipyretics,  depress  them.  (See  Loewi  and  also 
Chapter  XV.) 

BIBLIOGRAPHY 

Kanitz,  Aristides:  Z.  f.  Elektrochemie,  1907,  No.  44. 
Linser  u.  Schmid :  Deut.  Arch.  f.  klin.  Med.,  1904,  vol.  79. 
Loewi:  v.  Noorden's  Handb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2. 
Matthes:   Handb.  d.  Path.  d.   Stoffw.,  1907,  vol.  2. 
Rumpff:  Pfliiger's  Arch.,  1881,  vol.  33. 

2.  LIGHT  AND  RADIANT  ENERGY 

Natural  illumination  indirectly  exerts  an  influence  on  the  metabo- 
lism, inasmuch  as  through  the  eye  it  constantly  sends  sensory  im- 
pulses to  the  central  nervous  system,  as  a  result  of  which,  muscular 
tension  and  movements  are  excited  and  possibly  also  other  vital 
processes, — for  example,  the  formation  of  the  red  blood-cells  (Marti  u. 
Kronecker} . 

As  far  as  has  been  proven,  however,  only  the  blue-violet  and  ultra- 
violet rays  exert  a  direct  influence  on  the  chemism  of  the  cells  of 
the  higher  animals.  These  rays  exert  a  destructive  action  on  enzymes 
and  on  living  protoplasm,  just  as  they  do  on  all  chemically  labile 
substances.  This  power  is  systematically  employed  in  phototherapy, 
in  the  treatment  of  lupus,  cancer,  etc.,  according  to  such  methods  as 
that  of  Finsen,  and  by  means  of  especially  adapted  sources  of  light. 

Of  a  similar  nature  is  the  action  of  the  luminous  energy  absorbed 
by  fluorescent  substances.  Such  substances  as  quinine,  eosine,  acridine, 
etc.,  when  charged  with  this  energy,  as  long  as  they  remain  exposed 
to  light  decompose  living  protoplasm  and  other  very  susceptible  sub- 
stances, such  as  enzymes,  toxalbumins,  etc.  According  to  v.  Tappeiner 
and  Jodlbauer  and  to  Straub,  ionized  oxygen  is  probably  the  active 
agent  in  this  destructive  action.  In  therapeutics  this  property  of  these 
substances  may  be  utilized  by  such  methods  as  painting  0.1-0.5  per 
cent,  eosin  solution  on  those  portions  of  the  surface  of  the  body  where 
a  corrosive  effect  is  desired  and  exposing  them  to  sunlight. 

As  a  result  of  their  absorption  by  fluorescent  substances,  the  yel- 
low and  red  light  waves,  which  ordinarily  are  inert  chemically,  may 


LIGHT  AND  RADIANT  ENERGY  383 

be  rendered  chemically  active,  and,  as  these  rays  penetrate  vegetable 
and  animal  tissues  more  readily  than  the  violet  ones,  it  is  perhaps 
possible  for  them  to  produce  effects  in  the  interior  of  the  body  if  the 
tissues  are  impregnated  with  yellow  or  red  fluorescent  substances. 

Hsematoporphyrin,  a  haemoglobin  derivative  almost  constantly  found  in. 
human  urine,  is  markedly  fluorescent,  and  under  the  influence  of  light  exerta 
marked  hsemolytic  actions.  It  is  probably  constantly  present  in  the  mammalian 
organism,  although  normally  the  amount  present  is  extremely  small.  If  abnormal 
amounts  of  it  appear  in  the  blood,  those  portions  of  the  skin  which  are  exposed 
to  the  sun  may  become  diseased.  This  is  probably  the  cause  of  the  skin  lesions, 
in  hydroa  sestiva  (Hausmann) .  It  also  appears  probable  [?  TR.]  that  a  photo- 
dynamic  substance  present  in  the  corn  consumed  is  of  significance  in  connection 
with  the  skin  lesions  of  pellagra  (Horbaczewski,  Raubitschek,  Hausmann). 

RONTGEN  RAYS  AND  RADIUM  EMANATIONS. — Finally,  mention 
should  be  made  here  of  the  similarly  destructive  action  of  X-rays  and 
of  radium  emanations.  On  account  of  their  power  of  penetrating  the 
soft  parts  of  the  body,  their  action  is  not  confined  to  the  surface,  but 
also  affects  the  blood  and  tissues  in  the  interior  of  the  body.  Ex- 
posure to  them  results  in  a  destruction  of  the  red  cells  and  accumu- 
lation of  pigment  in  the  body,  and  more  especially  in  a  very  extensive 
destruction  of  myelocytes  and  lymphocytes  and  of  lymphoid  tissue. 
This  latter  action  has  been  utilized  in  the  treatment  of  leukgemia. 
Other  cells  also  of  embryonal  type,  such  as  the  germinal  cells  of  the 
sexual  organs  and  the  cells  of  pathological  new  growths,  are  readily 
affected  and  destroyed.  This  destruction  of  cells  results  in  an  in- 
creased decomposition  of  proteid  and  increased  excretion  of  nitrogen. 

Radio-active  Waters. — Radio-active  minerals  and  earths,  such  as. 
the  uranium  slag  from  the  mines  of  Joachimsthal,  when  placed  in 
water,  give  off  radio-active  emanations  to  it.  Consequently  the  waters 
of  many  springs  are  naturally  radio-active,  while  ordinary  water 
may  be  made  so  by  being  kept  for  many  hours  in  contact  with  radio- 
active material. 

Although  it  is  highly  probable  that  the  radio-activity  of  baths 
and  drinking  waters  can  exert  an  influence  on  the  human  organism, 
this  cannot  be  asserted  positively.  Clinical  experience,  however,  has 
led  to  the  belief  that  radio-active  waters  exert  a  beneficial  action  on 
rheumatic  and  other  similar  conditions.  It  has  been  possible  to  cause 
a  disappearance  of  uric  acid  from  the  blood  of  gouty  patients  and 
to  relieve  their  gouty  symptoms  by  causing  them,  for  several  hours 
daily  and  for  several  weeks,  to  inhale  air  charged  with  radium 
emanations.  According  to  Gudzent,  sodium  urate  is  changed  by  them 
into  other  more  soluble  substances.  This,  if  true,  would  explain  the 
absorption  of  the  uratic  deposits  and  the  disappearance  of  uric  acid 
from  the  blood.  (See  also  His,  Richet,  Loewenthal  u.  Wohlgemuth.) 

Nothing  is  known  about  the  direct  action  of  electric  energy  on  the 
metabolic  processes  of  the  cells. 


384  PHARMACOLOGY  OF  THE  METABOLISM 


BIBLIOGRAPHY 

Beil  u.  Raubitschek :   Wien.  klin.  Woch.,  1910,  No.  26. 

Gudzent:  Med.  Klinik,  No.  42. 

Hausmann,  W.:   Wien.  klin.  Woch.,  1910,  No.  36. 

Hausmann:   Die  sensibilisierende  Wirkung   des   Hamatoporphyrins.   Biochem.   z.. 

1910,  vol.  30,  p.  276. 

Heinecke:  Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1905,  vol.  14. 
His:  Med.  Klinik.,  1910,  No.  16. 
Horbaczewski :  Oesterr.  Sanitatswesen,  1910,  No.  31. 
Jodlbauer:  Jahrber.  Leist.  d.  physik.  Med.,  1908,  vol.  1,  p.  280. 
Loewenthal  u.  Wohlgemuth:      Biochem.  z.,   1909,  p.  476. 
Marcacci:  XII  Kongr.  Assoc.  med.  Ital.,  1887. 
Marti  u.  Kronecker:  Verh.  d.  XV  Kongr.  f.  inn.  Med.,  1897. 
Richet:  Arch,  intern,  d.  Physiol.,  1905,  vol.  3,  p.  130. 
Straub:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  51. 
V.  Tappeiner  u.  Jodlbauer:   Die  sensibilisierende  Wirkung  floureseieren  der  Sub- 

stanzen,  Leipzig,  1907. 

3.  WATER  AND  SALT  ACTIONS 

OSMOTIC  TENSION. — If  a  certain  number  of  gas  molecules  are  in- 
troduced into  a  vacuum  with  elastic  walls,  they  seek  to  increase  the 
volume  of  the  vacuum  by  distending  the  walls.  The  degree  of  this 
gas  pressure  is  proportional  to  the  number  of  molecules  in  the  unit 
of  space,  their  concentration,  and  to  the  absolute  temperature.  If  a 
given  number  of  molecules  or  ions  are  introduced  into  a  quantity  of 
water  surrounded  by  elastic  walls,  they  too  tend  to  increase  the 
volume  of  the  water  and  to  distend  the  containing  walls,  which  absorb 
the  water  on  the  outside  and  allow  it  to  enter  into  the  water  contained 
within  them.  This  water  absorbing  or  attracting  pressure  is,  like  the 
gas  tension,  proportional  to  the  concentration  of  the  molecules  or  ions 
in  solution  and  to  the  absolute  temperature.  The  passage  of  water 
through  the  membrane  is  called  osmosis  and  the  pressure  exerted  is 
called  osmotic  pressure  or  tension.  Gas  tension  and  osmotic  tension 
are  analogous. 

Isotonicity. — As  all  the  protoplasm  of  the  cells  of  the  animal 
body  is  more  or  less  permeable  to  water  and  is  bathed  in  watery 
media,  such  as  lymph,  blood-plasma,  etc.,  it  follows  that  the  osmotic 
tension — i.e.,  the  molecular  concentration  of  the  substances  which 
exert  osmotic  tension — must  be  the  same  in  the  cells  and  in  the  sur- 
rounding media,  for  otherwise  the  volume  of  the  cells  would  be  con- 
stantly changing.  The  cells  and  the  surrounding  media  must  be 
isosmotic  or  isotonic  to  each  other.  Actually  this  is  approximately  the 
case,  all  the  living  cells  of  the  mammal  having  the  same  osmotic  tension 
as  the  fluids  present  in  its  tissues.  This  tension  corresponds  closely 
to  that  of  0.9  per  cent.  NaCl  solution,  0.154  mols,  per  litre,  1  mol  or 
gramme  molecule  equalling  58.5  gm.  NaCl.  This  osmotic  tension  is 
due  only  in  the  slightest  degree  to  colloid  substances  (proteids,  etc.), 
being  almost  entirely  determined  by  dissolved  crystalloids,  chiefly  salts 
(the chlorides, carbonates,  and  phosphates  of  the  alkalies). 


WATER  AND  SALT  ACTIONS  385 

The  colloids  may  be  looked  upon  here  as  forming  a  sort  of  membranous 
framework  which  pervades  the  cells,  its  outer  layers  forming  an  external 
membranous  shell  which  may  be  considered  as  concentrically  continued  into  the 
interior  of  the  cells.  Most  animal  cells  lack  a  specially  differentiated  cell 
membrane. 

If  the  osmotic  tension  of  the  body  fluid  be  altered  by  the  introduc- 
tion of  water  or  of  salts,  a  difference  of  tension  between  them  and  the 
tissue  cells  results,  and  the  latter  will  contract  or  swell  up  according 
as  the  tension  is  increased  or  diminished.  However,  if  the  colloids 
of  the  cell  are  equally  permeable  to  the  molecules  in  solution  (salts, 
etc.)  and  to  water,  or  equally  impermeable  to  both,  its  volume  will 
remain  unchanged,  in  the  first  case  because  no  difference  in  tension 
arises  and  in  the  second  because  the  impermeable  walls  prevent  any 
equalization  of  the  tension. 

Slight  differences  in  tension,  such  as  arise  during  the  changing 
play  of  the  absorption  and  excretion  of  substances,  are  compensated 
for  by  the  cells  without  harm,  just  as  is  the  case  with  other  normal 
variations  in  the  conditions  of  life,  but  more  pronounced  and  espe- 
cially rapidly  produced  alterations  of  osmotic  tension  cannot  be  sup- 
ported without  injury. 

A  quite  gradual,  even  though  very  decided,  increase  of  the  osmotic  tension 
of  the  surrounding  medium  may  be  supported  by  vegetable  cells,  and  appaiently 
even  by  animal  cells,  for  they  are  able  to  accommodate  themselves  to  higher 
than  normal  osmotic  pressure  if  it  is  produced  gradually  enough. 

Alterations  of  the  osmotic  pressure,  which  under  some  circum- 
stances do  more  or  less  damage  to  the  cells,  may  be  produced  by  the 
introduction  of  large  quantities  of  pure  water  or  of  salts.  The  effects 
on  the  metabolism  express  themselves  by  an  increased  excretion  of  the 
decomposition  products  of  proteids,  especially  urea. 

PHARMACOLOGICAL  ACTIONS   OF  WATER 

LOCAL  EFFECT. — Pure  water  is  a  violent  poison  for  organism 
whose  cells  are  very  readily  permeable  to  it.  If  cephalopods  be  im- 
mersed in  distilled  water,  convulsive  movements  occur  and  death 
ensues  in  5-10  minutes  (Phisalix}. 

Injection  of  water  directly  into  the  circulation  is  followed  by  the 
passage  of  haemoglobin  into  the  plasma,  as  some  of  the  red  blood-cells, 
the  less  resistant  ones,  are  destroyed:  100-150  c.c.  per  kilo  will 
quickly  kill  dogs  and  rabbits,  while  even  30  c.c.  can  produce  fatal 
results  in  a  few  days  (Bosk  u.  Vedel). 

On  the  other  hand,  cells  which  are  less  permeable  are  much  more 
resistant  to  pure  water.  However,  the  disturbing  toxic  action  of 
pure  water  is  evidenced  even  in  the  mouth  by  a  flat,  disagreeable 
taste  and  in  the  nasal  and  pharyngeal  mucous  membranes  by  a  dis- 
tortion of  their  cells  when  pure  water  is  applied  to  them.  Pre- 
sumably the  superficial  epithelium  of  the  gastric  and  intestinal  rnucosa 
25 


386  PHARMACOLOGY  OF  THE  METABOLISM 

may  be  similarly  affected,  and  there  may  thus  result  an  accelerated 
casting  off  and  renewal  of  these  cells.  It  is  possible  that  such  effects 
may  play  some  role  in  the  treatment  of  gastric  catarrhs  by  lavage 
with  plain  water,  or  by  the  drinking  of  indifferent  waters,  such  as 
those  of  Gastein,  Wildbad,  and  many  other  springs. 

If  the  water  is  absolutely  pure,  it  is  claimed  that  the  local  osmotic  action 
may  be  so  great  that  serious  irritation  of  the  stomach  may  result.  To  such 
effects  Koppe  attributes  the  harmful  effect  of  swallowing  natural  ice,  which, 
in  contradistinction  to  artificial  ice,  contains  extremely  small  amounts  of  salts, 
and  also  that  resulting  from  drinking  the  waters  of  the  "  poison  spring "  in 
Gastein.  Whether  this  explanation  be  correct  or  not  is  uncertain. 

The  healthy  gastric  epithelium  is  almost  impassable  for  water  and 
for  salts,  and  therefore  within  wide  limits  is  unaffected  by  the 
osmotic  tension  of  the  gastric  contents.  Considering  the  fact  that 
food,  etc.,  must  often  remain  for  a  long  time  in  the  stomach,  it  is 
easy,  from  a  teleologic  point  of  view,  to  recognize  the  advantage 
of  this  insusceptibility.  "We  owe  our  knowledge  of  the  fact,  that 
water  and  substances  dissolved  in  water  are  hardly  at  all  absorbed 
by  the  gastric  mucosa,  originally  to  Hirsch,  whose  results  have  been 
confirmed  by  v.  Mering  and  by  Brandl. 

If  water  contains  alcohol  or  CO2,  it  is  absorbed  from  the  stomach. 
It  is  not  known  whether  these  substances  to  a  greater  or  less  extent 
loosen  the  lipoidal  cement  between  the  epithelium  or  whether  they 
render  the  epithelium  more  permeable  in  other  indirect  ways. 

In  the  intestines  water  is  rapidly  absorbed,  and,  as  a  rule,  is  al- 
most completely  excreted  by  the  kidney  in  the  course  of  several 
hours. 

EFFECTS  AFTER  ABSORPTION. — It  is  self-evident  that,  so  long  as  it 
remains  in  the  blood  and  the  tissues  or  is  passing  through  them,  pure 
water  will  reduce  their  osmotic  tension,  but  when  water  is  taken  at 
the  same  time  with  food,  even  when  several  litres  are  taken,  it  causes 
such  slight  changes  in  the  osmotic  tension  that  it  does  not  appreciably 
increase  tissue  change.  If,  however,  large  amounts  of  water  are  drunk 
during  a  period  of  fasting,  its  effects  on  the  osmotic  tension  of  the 
body  fluids  may  result  in  an  increased  decomposition  of  proteid  and 
of  fats  and  carbohydrates  (Heilner'}. 

It  is  not  possible  to  form  any  opinion  as  to  whether  or  not  such  a 
stimulation  of  metabolism  and  regeneration  plays  any  role  in  the 
effects  of  the  water-drinking  cures  which  have  been  widely  used  in  the 
treatment  of  many  chronic  diseases,  such  as  syphilis,  gout,  metallic 
poisonings,  etc.  In  any  case,  the  augmented  blood  and  lymph  flow, 
which  necessarily  result  from  the  drinking  of  large  amounts  of  water, 
must  be  of  some  significance  for  the  "  flushing  out"  of  the  body  and 
the  removal  of  metabolic  end  products. 

While  the  flooding  of  the  body  by  water  may  be  counteracted  by 


WATER  AND  SALT  ACTIONS  387 

increased  diuresis,  diaphoresis,  etc.,  the  converse  of  this — the  removal 
of  water,  or  dehydration,  by  thirst  cures — causes  an  osmotic  alteration 
in  the  opposite  direction,  which  cannot  be  relieved  by  physiological 
regulation,  and  consequently  its  effects  in  favoring  the  destruction 
and  regeneration  of  various  cells  are  more  energetic  and  persistent. 
In  Straub's  experiments  the  increased  nitrogen  excretion  persisted 
for  some  days  after  abandoning  the  limitation  of  the  water  intake 
(for  lit.  Magnus-Levy,  Dennig). 

BIBLIOGRAPHY 

Bosk  et  Vedel :  Arch,  de  Physiol.  norm,  et  path.,  Oct.,  1896. 

Denning:   Ztschr.  f.  diat.  Ther.,   1899. 

Heilner:   Ztschr.  f.  Biol.,  1907,  vol.  49. 

Hirsch:   Zentralbl.  f.  kl.  Med.,  1892,  No.  47. 

Hirsch:   Zentralbl.  f.  kl.  Med.,  1893,  No.  4,  18,  29. 

Koppe:  Deut.  med.  Woch.,   1898,  No.  39. 

Magnus-Levy:   Handb.  d.  Path.  d.  Stoffw.,  1906,  vol.  1,  p.  443. 

Phisalix:  Arch,  de  Physiol.  norm,  et  pathol.,  1892,  series  5,  vol.  4,  p.  217. 

Straub:   Ztschr.  f.  Biol.,  1899,  vol.  38. 

PHARMACOLOGICAL  ACTION  OF  NEUTRAL  SALTS 

Such  effects  are  produced  in  the  purest  form  when  water  is  ab- 
stracted from  the  tissue  cells  by  the  administration  of  salts  in  sub- 
stance or  in  hypertonic  solution.  This  has  been  experimentally 
proven  for  sodium  chloride,  nitrates,  acetates,  and  carbonates  (lit. 
Rost),  and  doubtless  holds  good  for  all  crystalloids  which  are  ab- 
sorbed by  the  blood,  in  so  far  as  the  tissue  cells  are  not  readily 
permeable  to  them  and  therefore  will  be  affected  by  changes  in  the 
osmotic  pressure  produced.  The  exact  manner  in  which  the  cells  are 
damaged  is  not  known,  but  it  should  be  remembered  here  that 
chemical  cleavage  reactions  may  be  caused  by  dehydration  through 
osmotic  action, — for  example,  fibrin  may  be  dissolved  with  the  for- 
mation of  globulin  and  albumoses  (Limbourg,  Dastre}. 

Accordingly,  it  is  more  than  probable  that  when  large  quantities 
of  sodium  chloride,  or  readily  absorbable  salts,  such  as  potassium 
iodide  or  bromide,  are  administered,  a  portion  of  the  curative  effects 
obtained  may  be  attributed  to  an  osmotic  stimulation  of  metabolism 
and  cell  regeneration.  However,  the  portion  of  the  curative  effects 
produced  can  hardly  be  very  large,  for  these  substances  are 
;ually  taken  with  large  amounts  of  water.  Moreover,  their  osmotic 
action  will  be  limited  further  by  the  fact,  still  unexplained,  that  the 
administration  of  salts  actually  causes  a  limitation  or  retardation  of 
proteid  metabolism,  if  enough  water  is  taken  at  the  same  time  with 
the  salts  to  prevent  any  dehydration  of  the  cells  (Rost):  Such  a 
retardation  or  limitation  of  the  catabolism  in  protoplasm  has  been 
roven  to  result  from  the  administration  of  different  sodium,  salts, 
asmuch  as  osmotic  action — i.e.,  a  dehydrating  action — has  been 
eluded,  such  effects  can  be  due  only  to  an  ion  action,  and  in  this 


aim 
thus 
usua 


388  PHARMACOLOGY  OF  THE  METABOLISM 

case  only  to  the  action  of  the  sodium  ions,  whose  concentration  in 
the  organism  has  been  increased  while  that  of  the  other  cations. 
K',  Mg',  Ca',  etc.,  present  in  the  body  has  not  been  altered. 

From  the  fundamental  investigations  of  Loeb,  Overton,  and  others,  we 
know  that  any  alteration  in  the  normal  cation  proportions  markedly  influences 
various  vital  phenomena.  If  this  interpretation  be  correct,  the  administration 
with  water  of  corresponding  amounts  of  the  salts  contained  in  Ringer's  solution  * 
should  cause  no  sparing  of  proteids  or  nitrogen  retention.  Otherwise  the  above- 
mentioned  effects  would  be  due  only  to  a  dilution  of  the  colloids  and  alteration 
of  the  viscosity,  the  effects  of  which  on  the  vital  processes  are  still  unknown. 

A  secondary  result  of  the  administration  of  neutral  salts  is  the 
loss  of  alkalies  by  the  body.  Salts  which  are  absorbed  with  difficulty 
(the  cathartic  salts,  salts  of  polybasic  acids),  as  a  result  of  their 
cathartic  action,  cause  a  loss  of  the  alkaline  intestinal  juices,  while 
readily  absorbable  salts  (those  of  the  sodium  chloride  group  and 
salts  of  the  monobasic  acids)  cause  a  distinct  but  much  smaller  loss 
of  alkalies  in  the  urine,  for  this  secretion  becomes  more  and  more 
strongly  alkaline  with  increasing  salt  diuresis  (Eudel}.  Whether  or 
not  the  continued  use  of  large  quantities  of  neutral  salts  results  in 
any  damage  to  the  organism  is  doubtful,  for  the  body  possesses  the 
means  of  protecting  itself  against  loss  of  its  alkalies  (see  below). 

All  the  same,  in  this  connection  it  is  noteworthy  that  the  long-continued 
use  of  the  natural  alkaline  cathartic  waters  is  better  borne  than  that  of  the 
neutral  ones,  and  that  the  continued  use  of  strongly  salted  food  appears  to  cause 
a  disposition  to  disease  (scurvy),  which  may  be  overcome  or  lessened  by  the 
consumption  of  fresh  vegetable  juices,  such  as  lemon  juice,  etc.,  which  contain 
salts  of  the  vegetable  acids  with  alkalies,  which  are  combusted  in  the  body 
with  the  formation  of  carbonates  and  therefore  act  like  the  alkalies.  It  is, 
however,  more  likely  that  this  curative  effect  in  scurvy  is  due  to  the  potassium 
ions  present  in  the  vegetable  juices  antagonizing  the  poisonous  action  of  the 
sodium  ions  with  which  the  body  is  flooded  as  a  result  of  consumption  of  salted 
foods  (Emmerich). 

The  salts  of  the  Glauber's  salt  group,  which  are  absorbed  with 
difficulty,  influence  the  metabolism  in  general  only  in  so  far  as  they 
cause  catharsis  and  thus  interfere  with  the  utilization  of  the  food. 
However,  the  bitter  waters  (magnesia  waters),  even  when  taken  in 
small  non-cathartic  doses,  diminish  the  absorption  of  the  fata 
(Vahlen),  probably  on  account  of  the  formation  of  insoluble  soaps 
with  magnesia. 

To  a  slight  extent  the  cathartic  salts  are  absorbed  in  the  small 
intestine,  and  of  this  amount  a  portion  is  excreted  again  into  the 
large  intestine  (Hay).  It  is  clear  that  during  this  passage  through 
the  portal  circulation  these  salts  may  exert  a  "  salt  action  "  on  the 
cells  of  the  liver  and  the  intestines,  and  this  may  in  part  account  for 
their  favorable  effects  in  diseases  of  the  intestines  and  liver. 

*  Ringer's  solution  for  mammals  contains  0.9  per  cent.  NaCl,  0.03  per  cent. 
NaHCO3,  0.042  per  cent.  KC1,  0.24  per  cent.  CaCl,. 


ALKALIES  389 


BIBLIOGRAPHY 

Dapper  u.  v.  Noorden:  Hdb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2. 

Dastre:  Arch,  de  Physiol.,  1895. 

Emmerich:   Pfiiiger's  Arch.,  1870,  vol.  3. 

Hay:  Journ.  of  Anat.  and  Physiol.,  1882. 

Limbourg:   Phys.  chem.,  1889,  vol.  13. 

Loeb,  J.:   Biochem.  Ztschr.,   1911,  vol.  31,  p.  450. 

Host:  Arb.  d.  Kais.  Ges.,  1901,  vol.  18. 

Riidel:  Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30. 

Vahlen:  Ther.  Monatshefte,  1898,  vol.  12. 

ALKALIES 

Among  the  salts,  those  reacting  alkaline  occupy  a  special  position. 
Such  are  the  basic  salts  or  the  salts  of  the  weak  acids  such  as  the 
carbonates.  The  free  alkalies,  in  respect  to  their  action  in  the 
organism,  are  also  to  be  considered  as  belonging  to  this  group. 

In  this  connection  the  basic  phosphates  and  the  carbonates,  the 
weak  alkalies,  such  as  Ca(OH)2  and  Mg(OH)2,  the  salts  of  the 
alkalies  with  vegetable  acids,  which  are  oxidized  in  the  organism  to 
carbonates,  and,  finally,  the  borates  are  of  practical  importance. 

REACTION  OP  THE  BLOOD. — Blood  and  lymph  always  contain  large  amounts 
of  indifferent  carbon  dioxide,  of  which  a  portion  is  present  in  the  form  of 
carbonic  acid,  corresponding  in  amount  to  the  quantity  of  the  alkalies  in 
solution.  Therefore  in  a  theoretical  sense  blood  and  lymph  are  necessarily 
neutral.* 

Potentially,  however,  the  blood  is  both  acid  and  alkaline,  and  may  be 
stated  to  be  amphoteric,  inasmuch  as,  without  losing  its  theoretically  neutral 
reaction,  it  may  absorb  acids  or  alkalies,  in  the  first  case  the  CO3'  ions  being 
liberated  from  their  original  combinations,  in  the  second,  the  C02  which  is 
always  present  being  utilized  to  combine  with  the  bases  absorbed.  Moreover, 
not  only  the  carbon  dioxide  but  also  the  latent  H'  ions  of  the  blood  proteids 
may  be  brought  into  action  by  the  addition  of  alkalies,  while,  on  the  other 
hand,  by  the  addition  of  acids  both  of  these  may  again  be  rendered  inactive  or 
latent.  Even  in  the  presence  of  grave  or  fatal  acid  intoxication,  the  reaction 
of  the  blood  consequently  remains  almost  normal  (Benedikt,  Szili,  Robertson'). 
It  is  thus  evident  that  the  determination  of  the  reaction  of  the  blood  by  the 
use  of  different  dyes  as  indicators  can  give  only  values  which  are  physiologically 
incorrect  (H.  Meyer,  Henderson}.  To  litmus  the  blood-plasma,  outside  of  the 
body,  reacts  alkaline,  because  this  acid  possesses  a  stronger  affinity  for  the  bases 
than  carbonic  acid  and  the  acid  proteids  of  the  plasma,  and  consequently  deprives 
them  of  their  alkalies,  with  which  it  forms  blue-colored  salts. 

INCREASED  ALKALINITY. — As  many  chemical  processes,  particularly 
oxidation, — e.g.,  that  of  glucose, — are  either  accelerated  by,  or  only 
possible  in  the  presence  of,  free  OH'  ions,  it  would,  a,  priori,  appear 
probable  that  the  administration  of  alkalies  would  stimulate  oxida- 
tion in  the  animal  organism  as  a  result  of  augmentation  of  the  car- 

*  Inasmuch  as  in  the  presence  of  a  high  CO3  tension  traces  of  free  carbonic 
acid  are  present  in  an  aqueous  solution,  the  plasma  may  contain  traces  of 
free  H'  ions,  and  consequently,  theoretically,  may  be  very  slightly  acid.  The 
eame  holds  true,  however,  also  for  the  potentially  basic  proteids  of  the  plasma, 
so  that  free  HO'  ions  may  also  be  present,  and  exact  determinations  have 
shown  that  in  the  blood-plasma  there  is  an  exceedingly  small  excess  of  the 
free  HO'  ions. 


390  PHARMACOLOGY  OF  THE  METABOLISM 

bonate  alkalinity  of  the  protoplasm.  This  presumption,  even  if  it 
should  be  correct,  is  distinctly  limited  in  its  significance  by  the  fact 
that,  in  the  normal  organism,  it  is  not  possible,  even  by  the  admin- 
istration of  alkalies  in  large  quantities,  to  increase  the  alkalinity  of 
the  blood  for  any  length  of  time,  for  any  carbonate  in  excess  of  the 
normal  is  almost  immediately  excreted  by  the  kidney  and  the  in- 
testines (Baimond,  Freudberg).  Moreover,  it  is  altogether  un- 
certain to  what  extent  and  how  rapidly  the  cell  protoplasm  itself 
takes  any  part  in  temporary  alterations  of  the  alkalinity  of  the  blood 
and  lymph,  a  participation  that  evidently  would  be  of  essential  im- 
portance. 

ACTION  OF  ALKALIES  ON  METABOLISM. — It  has  been  claimed  that 
the  catabolism  of  proteids  and  of  fats  is  influenced  by  the 
alkalies,  but  the  experiments  on  animals  and  on  men  undertaken  for 
the  purpose  of  investigating  such  action  have  given  contradictory 
results,  which  are  also  not  free  from  ambiguity  in  their  significance, 
inasmuch  as  the  "  alkali  action  "  cannot  be  sharply  differentiated 
from  the  accompanying  "  salt  action."  No  specific  effects  on  the 
decomposition  of  proteids,  including  the  metabolism  of  purins,  nor 
on  the  carbohydrate  metabolism,  have  been  definitely  proven  to  result 
from  the  administration  of  alkalies,  with  the  single  exception  that 
proteid  anabolism  is  temporarily  retarded,  but  this  is  compensated 
for  in  the  later  periods  of  the  experiment.  On  the  other  hand,  J.. 
Loewy  's  experiments  indicate  that  it  is  probable  that  the  alkalies  exert 
a  stimulating  effect  on  the  oxidation  of  fat,  and  Eubner  and  Eost 
have  definitely  proven  that  the  borates  do  exert  such  an  influence. 

This  is  in  agreement  with  the  well-known  reducing  effect  of 
Carlsbad  and  similar  alkaline  saline  waters.  On  the  other  hand,  it 
appears  that  under  some  conditions  certain  other  oxidative  processes 
may  be  inhibited  by  the  alkalies,  for  following  the  ingestion  of  large 
amounts  of  sodium  carbonate  or  citrate  (20-30  gm.  per  diem)  more 
"  neutral  "  and  less  "  oxidized  "  sulphur  is  excreted  in  the  urine 
(Jawein}. 

Alkalies  in  Gout. — The  manner  in  which  the  alkalies  produce  their 
reputed  favorable  action  in  gout  is  still  unknown.  So  long  as  it  was 
believed  that  gout  was  due  to  a  retention  of  uric  acid  resulting  from 
unfavorable  conditions  for  its  solution  and  the  consequent  difficulty 
with  which  it  could  be  excreted  through  the  kidney,  it  was  natural 
to  explain  the  value  of  the  alkalies  by  their  supposed  power  of  bring- 
ing uric  acid  into  solution.  This  explanation  is,  however,  certainly 
incorrect,  for  such  action  cannot  occur  under  the  conditions  which 
obtain  in  the  organism  (Gudzent).  Further,  the  recent  exhaustive 
investigations  of  Brugsch  and  Schittenhelm  have  rendered  it  ex- 
tremely probable  that  in  gout  it  is  not  the  insolubility  or  the  faulty 
excretion  of  uric  acid,  but  a  retardation  of  its  formation  or  destruc- 
tion on  account  of  a  defective  ferment  activity,  which  is  the  decisive 


ALKALIES  391 

pathogenic  factor.  In  addition,  exact  investigations  of  the  effect 
of  the  administration  of  alkalies  on  the  excretion  of  uric  acid  in 
gout  have  given  results  which  are  by  no  means  lacking  in  ambiguity 
(v.  Noorden),  but  in  the  majority  of  instances  the  excretion  of  uric 
acid  was  not  affected.  For  these  various  reasons,  it  is  exceedingly 
doubtful  whether  the  alkalies  in  any  way  affect  the  metabolism, 
solubility,  or  excretion  of  uric  acid.  The  inclination  of  clinicians  is 
rather  to  explain  the  unquestionably  beneficial  action  of  alkalies  in 
gout  by  their  curative  action  on  disturbances  of  the  alimentary  canal 
and  the  liver,  which  quite  often  are  present  in  this  disease  (v. 
Noorden). 

Urolytic  Action  of  Alkalies. — On  the  other  hand,  the  value  of  the 
alkalies  in  the  treatment  of  uratic  deposits  in  the  urinary  tract  is 
well  established  and  is  doubtless  due  to  the  increased  alkalinity  of 
the  urine  thus  caused.  This  increase  need  not  be  so  great  as  to  cause 
the  urine  to  render  red  litmus  paper  blue,  but  it  may  always  be 
recognized  by  the  relative  increase  of  the  disodium  phosphate  as 
compared  with  that  of  the  acid  monosodium  phosphate.  The  bene- 
ficial effect  of  this  increase  in  the  alkalinity  of  the  urine  is  evidenced 
by  the  fact  that  often  after  a  short  time  small  pieces  of  the  con- 
cretions are  passed  out  with  the  urine,  and  that  very  often  the 
excretion  of  uric  acid  is  increased  (v.  Noorden).  Among  the  alkalies, 
the  alkaline  earths  appear  to  be  especially  useful  for  this  indication, 
and,  among  these,  calcium  appears  to  be  the  best,  on  account  of  the 
fact  that  it  is  free  from  any  disturbing  side  actions,  with  the  ex- 
ception of  the  very  occasional  formation  of  large  fecal  concretions. 

These  alkaline  earths,  especially  chalk  and  magnesia,  combine  with 
fatty  acids  and  with  sulphuric  and  phosphoric  acids  in  the  intestine, 
and  consequently  the  urine  becomes  alkaline  and  at  the  same  time 
contains  less  sulphates  and  less  phosphates, — i.e.,  less  salts, — so  that 
its  molecular  concentration  falls.  This,  too,  is  of  material  importance 
for  the  more  ready  solution  of  the  urates,  and  sufficiently  explains 
value  of  these  alkalies  and  of  the  waters  containing  them 

ildungen,  Fachingen,  etc.)  in  the  treatment  of  uratic  deposits  in 

urinary  tract  (Caulet,  J.  Strauss'). 

EFFECTS  ON  THE  ALKALINITY  OF  THE  BLOOD. — Although,  as 
previously  stated,  the  normal  alkalinity  of  the  blood  cannot  be  ap- 
preciably augmented  by  the  administration  of  the  alkalies,  it  is  quite 
otherwise  in  the  presence  of  abnormally  diminished  alkalinity  of  the 
blood,  such  as  occurs  in  exogenous  and  endogenous  acid  intoxication. 

Carnivorous  animals,  and  to  some  extent  also  vegetarian  animals 
and  man,  are  able  to  protect  the  alkaline  carbonates  and  albuminates 
of  their  blood  from  decomposition  by  acids,  by  utilizing  the  ammonia, 
nned  during  the  breaking  down  of  proteids,  for  the  neutralization 

any  abnormal  amounts  of  acid,  instead  of  transforming  it  as  usual 

o  carbamic  acid  and  urea.     This  is  the  explanation  for  the  fact 


392  PHARMACOLOGY  OF  THE  METABOLISM 

that  the  quantity  of  ammonia  excreted  in  the  urine  is  invariably  in- 
creased in  acid  intoxication  of  any  type  (Loewi).  However,  this  pro- 
tective  regulation  of  the  organism  is  a  limited  one,  and,  if  enough 
acid  be  administered  or  produced,  it  may  be  so  inadequate  that  the 
carbonate  alkalescence  of  the  blood  will  be  decidedly  diminished. 

This  occurs  in  diabetic  coma  as  a  result  of  the  formation  of  oxy- 
butyric  acid,  or  when  abnormal  amounts  of  lactic  acid  are  formed  as 
a  result  of  excessive  muscular  exertion,  and  in  many  poisonings, 
such  as  those  produced  by  arsenic,  phosphorus,  etc.,  and  in  the 
toxaemia  of  fever.  F.  Kraus  found  the  alkalinity  of  the  blood,  in 
terms  of  the  C02  removable  by  the  vacuum  pump,  diminished  to  y2 
or  %  of  the  normal  in  typhoid  fever,  erysipelas,  and  scarlatina,  and  in 
tuberculosis  with  continuous  fever.  As  this  diminution  of  the  alka- 
linity persists  in  such  cases  even  when  the  temperature  is  artificially 
lowered,  it  is  evident  that  it  does  not  depend  on  the  increased  tem- 
perature but  is  due  to  the  toxic  decomposition  of  proteids.  The  deficit 
in  alkaline  carbonates  in  the  blood  and  its  more  or  less  harmful 
effects  may  be  lessened  or  removed  by  the  administration  of  the 
alkaline  salts  of  the  vegetable  acids,  the  citrates  being  especially 
adapted  for  this  purpose,  as  they  are  almost  completely  combusted 
in  the  body  with  the  formation  of  carbonates. 

Especially  in  severe  diabetes  mellitus  large  amounts  of  oxy- 
butyric  acid  are  formed  which  greatly  diminish  the  alkalinity  of  the 
blood  by  expelling  the  combined  carbonic  acid.  In  extreme  cases, 
instead  of  30-36  per  cent,  by  volume,  Kraus  found  only  12.4  and 
9.8  per  cent  of  carbonic  acid  in  the  venous  blood,  while  Minkowski 
found  as  little  as  3.3  per  cent.  It  is  clear  that  in  such  cases  the  ad- 
ministration of  alkalies  will  be  beneficial  and  even  life  saving 
(Magnus-Levy}.  It  is  claimed  that  calcium  carbonate  and  phosphate 
exert  an  especially  favorable  influence  in  diabetes.  In  addition  to 
their  action  as  alkalies,  their  value  is  probably  in  part  due  to  the 
fact  that  the  diabetic  appears  to  lose  his  calcium  more  readily  than 
the  other  alkalies  and  therefore  has  a  greater  need  for  this  particular 
element  (Schlesinger  u.  Gerhardt.) 

OTHER  ACTIONS  OP  THE  ALKALIES. — In  addition  to  the  effects  on 
metabolism  discussed  above,  the  alkalies  by  their  local  actions  produce 
a  number  of  therapeutically  important  effects.  Concentrated  potas- 
sium hydrate  solutions  decompose  and  destroy  organic  substances, 
even  such  resistant  ones  as  the  horny  structures  of  the  skin,  in  which 
process  their  power  of  saponifying  and  dissolving  the  protective  fat 
in  the  skin  is  of  more  or  less  assistance.  They  are,  therefore,  used 
externally  in  different  concentrations  as  caustics  and  as  means  of 
irritating,  softening,  or  cleaning  the  skin.  Vienna  caustic  paste, 
potassium  soaps,  sodium  hydrate,  and  potash  may  be  used  as  counter- 
irritants  or  as  disinfectants  in  scabies.  Sodium  soaps  are  used  for 
cleansing  purposes  or  as  mild  irritants  in  enemata.  Borax  may  be 


ACIDS 

employed  as  a  lotion  or  in  mouth  washes.  Internally  dilute  solutions 
of  the  alkaline  carbonates  or  of  Ca(OH)2,  compound  chalk  powder, 
magnesium  oxide,  may  be  used  for  the  direct  neutralization  of  acids 
in  the  stomach  or  intestines  or  to  stimulate  [?  TR.]  the  gastric  diges- 
tion (Pawlow)  or  to  dissolve  mucus  (see  Pharmacology  of  the  Diges- 
tion, p.  165). 

BIBLIOGRAPHY 

Benedikt:   Pfliiger's  Arch.,  1906,  vol.  115,  p.  106. 

Brugsch:   Hdb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2,  p.  570. 

Caulet:   Bull.  gen.  de  Th6r.,   1875. 

Caulet:  Med.   Zentralbl.,    1875,  vol.   13,   p.   908. 

Freudberg:   Virchow's  Arch.,   1891,  vol.    125. 

Gudzent:   Physikal.   Chem.  d.  Harnsaure,  Zentralbl.   f.  d.  ges.  Physiol.  u.   Path. 

d.  Stoffw.,  1910,  No.  8. 
Henderson:   Erg.  d.  Physiol.,  1909,  p.  254. 
Jawein:   Ztschr.  f.  klin.  Med,  1893,  vol.  22. 
Kraus:   Ztschr.  f.  Heilk.,  1889,  vol.  10. 

Loewi:  v.  Noorden's  Hdb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2,  p.  673. 
Loewy,  A.:   Dubois'  Arch.,  1903,  vol.  378. 
Magnus-Levy:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42. 
Meyer,  H.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1883,  vol.  17,  p.  304. 
Minkowski:  Mitt.  a.  d.  Med.  Klin,  zu  Konigsberg,   1888. 
v.  Noorden:    Sammlung  klin.  Abh.  ii.  Therap.  u.  Path.,  1909,  Nos.  7  and  8. 
Pawlow:   Die  Arbeit  d.  Verdauungsdriisen,  Wiesbaden,  1898,  pp.  192,  193. 
Raimond:   Ann.  univ.  d.  med.  e  chir.,   1884,  vol.  299. 
Robertson,  Br.:   Jour,  of  Biol.  Chem.,  vol.  6,  p.  313. 
Rubner  u.  Rost:  Arb.  d.  Kais.  Gesundheitsamtes,   1902,  vol.   19. 
Schlesinger  u.  Gerhardt:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  42. 
Stadelmann :  Ueber  d.  einfl.  d.  Alkalien  a.  d.  Stoffw.,  Stuttgart,  1890. 
Strauss,  J.:  Ztschr.  f.  klin.  Med.,  1897,  vol.  31. 
Szili:  Pfluger's  Arch.,  1906,  vol.  115,  p.  82. 

ACIDS  AND  ACID  SALTS 

The  administration  of  acids  may  affect  the  gastric  and  intestinal 
digestion  and  in  this  way  influence  the  metabolism  (for  details  see 
Pharmacology  of  the  Digestion,  p.  165).  During  and  after  their 
absorption  they  neutralize  the  alkalies  of  the  blood  and  of  the  tissues, 
and  thus  diminish  their  normal  content  of  alkaline  carbonates  and 
albuminates  in  so  far  as  ammonia  by  its  vicarious  action  does  not  pre- 
vent this.  A  priori  it  is  probable  that  the  metabolic  processes  will  be 
affected  by  such  diminution  of  the  alkalinity  of  the  tissues,  and  that 
this  is  so  is  indicated  by  the  manner  in  which  autolysis  is  influenced 
by  diminished  alkalinity.  Post-mortem  autolysis  of  the  organs,  which 
appears  to  resemble  closely  the  catabolic  processes  of  life,  is  markedly 
influenced  by  the  reaction  of  the  surrounding  medium,  alkalinity, 
corresponding  about  to  that  of  normal  serum,  strongly  inhibiting  it 
and,  on  the  other  hand,  a  slight  acidity  markedly  accelerating  it 
(Hedin  u.  Rowland,  Wiener,  Loeb  u.  Bar) . 

In  accordance  with  this,  an  increased  destruction  of  proteids  would 
be  expected  to  result  from  the  administration  of  acids,  and,  as  a 
matter  of  fact,  this  effect  has  been  observed  in  men  who  had  taken 
inorganic  acids  in  small  amounts,  for  they  excreted  not  only  more 
alkalies  and  ammonia  but  also  more  sulphuric  and  phosphoric  acids 


394  PHARMACOLOGY  OF  THE  METABOLISM 

than  normally  (A.  Keller,  Dunlop).  In  severe  acid  intoxication  (in 
rabbits)  the  production  of  heat  is  diminished  and  there  is  a  lessened 
formation  of  carbonic  acid  and  a  diminished  consumption  of  oxygen 
(Chvostek). 

From  these  results  and  from  what  has  been  said  previously  it 
might  be  concluded  that  the  proteid  metabolism — i.e.,  its  decom- 
position and  cleavage — is  retarded  by  the  alkaline  carbonates  of  the 
blood,  while  oxidative  processes,  such  as  the  combustion  of  the  fats 
and  carbohydrates,  are  accelerated,  and  that,  on  the  other  hand,  a 
diminution  of  the  alkalinity  of  the  blood  by  either  exogenous  or 
endogenous  acids  has  the  opposite  effect.  Such  endogenous  acidifica- 
tion, due  chiefly  to  the  formation  of  lactic  acid,  always  occurs  when 
the  tissues  are  very  inadequately  supplied  with  oxygen,  either  on 
account  of  an  insufficient  transportation  of  the  oxygen  by  the  blood 
or  on  account  of  chemical  inhibition  of  the  oxidases  of  the  tissues. 
Such  disturbances  will  necessarily  also  influence  metabolism  in  a  cor- 
responding fashion,  and  in  extreme  cases  will  cause  on  the  one  hand 
increased  destruction  of  the  tissues  and  on  the  other  fatty  degenera- 
tion (A.  Frdnkel,  M.  Fisher). 

Besides  producing  an  alteration  of  the  metabolism,  the  neutraliza- 
tion of  the  alkaline  carbonates  of  the  blood  which  occurs  in  extreme 
acid  intoxication  has  an  extremely  harmful  effect  on  all  nervous 
organs,  the  vasomotor  centres,  the  respiratory  centre,  and  the  motor 
ganglia  of  the  heart  being  depressed  or  paralyzed.  Under  such  con- 
ditions the  intravenous  injection  of  sodium  carbonate  may,  even  at 
the  last  moment,  have  a  life-saving  effect. 

LOCALLY,  concentrated  acids  produce  a  caustic  and  destructive 
effect  on  the  tissues,  while  dilute  acids  cause  slight  irritation  or 
stimulation  or  produce  an  astringent  action  and  may  be  used  thera- 
peutically  for  such  effects.  Those  acids  which,  on  account  of  their 
lipoid  solubility,  readily  penetrate  the  skin,  such  as  acetic  and  formic 
acids,  are  especially  useful  as  skin  irritants.  Sulphuric  acid  and 
others  may  be  used  in  the  form  of  baths  for  similar  purposes. 

CARBON  DIOXIDE  AS  A  STIMULANT  TO  THE  NERVOUS  SYSTEM. — 
Among  the  acids,  carbonic  acid  occupies  a  peculiar  position.  In  so 
far  as  it  reacts  with  free  alkalies  or  with  those  combined  with  the 
weaker  acids  (albuminates)  it  acts  as  an  acid.  In  addition  it  acts 
as  neutral  C02  which  is  always  present  in  the  tissues  and  in  the 
blood,  in  which  form  it  produces  stimulating  and  depressing  effects 
just  as  do  other  neutral  substances  which  are  soluble  in  water  and 
lipoids, — i.e.,  the  substances  belonging  to  the  group  of  ether  and 
alcohol.  The  normal  C02  tension  of  the  tissues,  which  amounts  to 
about  6  per  cent,  of  an  atmosphere,  is  of  decisive  significance  for  the 
maintenance  of  the  normal  excitability  of  the  tissue  cells  and,  as  a 
matter  of  fact,  is  an  absolutely  necessary  condition  for  its  main- 
tenance. If  as  a  result  of  too  extreme  ventilation  of  the  lungs  the 


THYROID  SUBSTANCES  395 

carbon  dioxide  tension  falls  markedly,  acapnia  results  and  the  nervous 
system  loses  its  excitability,  and  collapse  and  shock  develop  (Y. 
Henderson}, 

A.  Mosso  at  one  time  attributed  the  phenomena  of  mountain  sickness  to 
such  a  deficiency  of  carbon  dioxide,  but  did  so  incorrectly,  as  has  been  shown 
by  both  older  and  newer  investigations  (Zuntz,  Loewi,  Miller  u.  Caspari,  Boycott 
and  Haldane). 

If,  on  the  other  hand,  as  a  result  of  relatively  or  absolutely  in- 
sufficient elimination  by  the  lungs,  the  carbon  dioxide  content  of  the 
blood  is  increased  beyond  the  normal,  restlessness  and  excitation 
of  the  respiratory  and  vasomotor  centres  develop,  while,  if  the  increase 
be  great  enough,  deep  narcosis  is  caused. 

BIBLIOGRAPHY 

Boycott  and  Haldane:  Jour,  of  Physiol.,  1908,  vol.  37,  p.  355. 

Chvostek:   Zentralbl  f.  inn.  Med.,  1893,  vol.  14. 

Dunlop:  Journ.  of  Phys.,  1896,  vol.  20. 

Fischer,  M.:   Das  Odem.    German  transl.  by  Schorr  u.  Ostwald,  1910. 

Frankel,  A.:   Virchow'a  Arch.,   1876,  vol.   67. 

Hedin  and  Rowland:   Ztschr.  f.  phys.  Chem.,  1901,  vol.  32. 

Henderson,  Yandell:  Am.  Journ.  of  Physiol.,  1907,  vol.  21;    1909,  vols.  23  and 

24;  1910,  vols.  25,  26,  and  27. 
Keller,  A.:  Jahrb.  f.  Kinderheilk.,  1897. 

Loeb  u.  Bar:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  51. 
Wiener:   Zentralbl.  f.  Phys.,   1905,  vol.  19. 
Zuntz,  Loewy,  Miiller  u.  Caspari:     Das  Hbhenklima,  Berlin,  1906. 

THYROID  SUBSTANCES 

IODOTHTRIN,  OR  THYROiooiN,  an  iodine-containing  substance,  was 
first  prepared  from  the  thyroid  glands  by  Baumann  in  1896.  It  is 
obtained  from  a  proteid  containing  iodine,  thyroglobulin,  by  the 
action  of  heat  and  hydrochloric  acid.  In  all  probability  this  iodine- 
globulin  is  a  secretion  of  the  thyroid  glands  which  enters  the  blood 
and  exerts  an  important  influence  on  the  normal  growth  and  death 

the  cells  of  all  the  organs  of  the  body.    It  is  for  our  present  purpose 

little  importance  whether  this  internal  secretion  or  hormone  pro- 
uces  this  "  life-stimulating  "  action  directly  by  a  catalytic  accelera- 
tion of  chemical  reactions  *  or  indirectly  by  destroying  an  inhibiting 
fbstance.  Thus  far  there  is  no  evidence  which  forces  the  acceptance 

this  latter  assumption,  the  "  detoxication  "  hypothesis,  f 

*  Recently  L.  B.  Stookey  and  Vera  Gardner  have  reported  that  the 
autolysis  of  organs  obtained  from  dogs  thyroidectomized  5  to  10  days  earlier 
proceeds  more  slowly  than  that  of  the  organs  obtained  from  normal  animals. 
They  also  state  that  the  oxidizing  power  of  such  organs,  estimated  by  the 
oxidation  of  indol  added  to  an  emulsion  of  the  organs,  is  weaker  than  that 
of  emulsions  of  the  normal  liver,  spleen,  and  kidney.  Moreover,  both  the 
autolysis  and  the  oxidizing  power  can  be  distinctly  increased  if  normal  dogs 
be  treated  for  a  long  time  previously  with  KI,  probably  as  a  result  of  an 
increased  function  of  the  thyroid  glands  (see  the  section  dealing  with  iodine, 
p.  398). 

t  For  the  influence  of  the  thyroid  glands  or  iodothyrin  on  the  functions  of 
e  heart  and  vessels  see  v.  Cyon,  Die  Gefassdriisen,  Berlin,  1910,  and  Biedl, 
:-  innere  Sekretion,  Wien,  1910. 


aii 

? 

du 


396  PHARMACOLOGY  OF  THE  METABOLISM 

IN  HYPOTHYROIDISM. — If  the  thyroids  be  absent,  as  in  thy- 
reopriva,  cachexia  strumipriva,  or  myxoedema,  or  if  they  be  de- 
generated, as  in  endemic  cretinism,  the  formation  of  the  blood  and 
the  general  growth  are  retarded  and  more  or  less  complete  myxoedema 
develops.  Under  such  conditions  the  transformation  of  energy  and 
the  tissue  change  may  be  diminished  to  as  little  as  %  of  the  normal 
(Magnus-Levy}.  If,  however,  iodothyrin  be  administered  to  such  in- 
dividuals, the  transformation  of  energy  and  the  metabolism  both 
rise  to,  and  in  fact  at  times  above,  normal  levels,  and  those  cases  in 
which  development  had  ceased  or  in  which  atrophy  has  occurred 
regain  the  capacity  of  active  growth  and  regeneration.  As  a  result 
of  such  observations,  of  similar  significance  whether  made  on  animals 
or  on  human  beings,  there  can  be  no  doubt  that  iodothyrin  possesses 
the  property  of  truly  stimulating  metabolism, — i.e.,  of  stimulating 
both  the  anabolism  and  catabolism  of  the  cell  protoplasm, — and  this 
stimulation  apparently  affects  all  types  of  cells,  including  the  cells 
of  the  nervous  system.  The  successful  treatment  of  infantile  creti- 
nism and  of  myxcedema  by  thyroid  preparations  is  one  of  the  most 
brilliant  therapeutic  achievements  which  have  been  rendered  possible 
as  the  result  of  experimentation. 

Parathyroids. — Cachexia  strumipriva,  following  the  extirpation  of  goitrous 
thyroids,  is  complicated  by  tetany  only  in  case  the  parathyroids  have  also  been 
removed  or  if  they  have  been  so  injured  during  the  operation  that  they  de- 
generate in  their  entirety.  In  this  serious  condition  the  administration  of 
thyroid  glands  is  of  no  avail,  nor  does  any  benefit  result  from  administering 
parathyroid  tissue  internally,  subcutaneously,  or  intravenously  (Pineles).  The 
parathyroids  appear  to  be  capable  of  performing  their  functions  only  when 
undisturbed  in  their  own  proper  situation.  Their  function  is  probably  that 
of  rendering  harmless  certain  unknown  metabolic  products. 

IN  NORMAL  ANIMALS  AND  HUMAN  BEINGS,  the  administration  of 
iodothyrin  causes  a  similar  stimulation  of  the  metabolism,  although 
naturally  not  to  the  same  extent  as  in  those  cases  where  the  function 
of  the  thyroid  was  previously  entirely  lacking  or  very  insufficient. 
In  many  cases  the  normal  optimal  total  transformation  of  energy  can- 
not be  augmented,  but  in  others  by  continuous  administration  of 
iodothyrin  for  2  to  3  weeks  it  can  be  increased  about  2.5  per  cent. 
Regularly  and  from  the  start  the  excretion  of  nitrogen  is  increased 
by  the  administration  of  iodothyrin,  as  a  result  of  a  more  active 
decomposition  of  proteid  material.  Consequently  the  nitrogen  bal- 
ance becomes  negative  and  a  loss  of  weight  results  (for  lit.  see 
Magnus-Levy}. 

IN  OBESITY. — The  augmentation  of  oxidation  by  thyroiodin  has 
been  observed  especially  often  and  in  high  degree  in  obese  individuals, 
in  whom  it  is  not  seldom  accompanied  by  marked  loss  of  fat.  This, 
however,  by  no  means  holds  good  for  all  obese  patients,  and  especially 
not  for  those  in  whom  there  is  no  pathological  disturbance  of  meta- 
bolism but  who  have  become  fat  essentially  as  a  result  of  overeating. 


THYROID  SUBSTANCES  397 

It  appears  that  this  increase  of  fat  combustion  occurs  especially  in 
constitutionally  obese  individuals  who,  in  spite  of  scanty  diet  and 
exercise,  are  unable  to  burn  up  their  fat.  One  is  tempted  to  assume 
that  in  these  cases  the  abnormal  metabolism  is  due  to  a  partial  in- 
sufficiency of  the  thyroid  function  or  that  of  other  glands  whose 
functions  are  of  a  similar  nature.  If  this  be  so,  the  success  of  the 
treatment  with  thyroid  glands  explains  itself. 

The  exaggerated  production  and  accumulation  of  fat,  when  the  thyroid  is 
insufficient  or  absent,  appears  to  be  due  not  only  to  the  general  retardation  of 
oxidative  processes  but  more  particularly  to  the  facilitation  of  the  transforma- 
tion— i.e.,  the  reduction — of  the  carbohydrates  to  fats,  which  results  from 
this  inadequacy  of  these  glands.  Certain  clinical  observations  render  it  probable 
that  the  functionally  active  thyroid  moderates  or  inhibits  this  normal  trans- 
formation of  the  carbohydrates  to  fats,  for  not  infrequently,  especially  in  obese 
patients  who  are  predisposed  to  diabetes,  the  administration  of  thyroid  pre- 
parations causes  glycosuria  (v.  Noorden). 

SYMPTOMS  OF  IODOTHYRIN  POISONING. — A  number  of  different  dis- 
turbances— rush  of  blood  to  the  head,  palpitation  and  acceleration  of 
the  heart,  dyspnoea,  sleeplessness,  tremor,  thirst,  subjective  feelings 
of  heat,  excessive  sweating,  swelling  of  the  neck,  and  exophthalmos — 
have  been  observed  to  follow  immoderate  or  careless  administration  of 
iodothyrin  to  susceptible  individuals.  These  are  all  symptoms  which 
are  characteristic  of  the  picture  of  Graves 's  or  Basedow's  disease. 
This  similarity  in  the  symptoms  of  the  poisoning  with  iodothyrin  to 
the  symptoms  of  this  disease  is  not  only  a  superficial  one  but  is  one 
based  on  the  similar  nature  of  the  two  conditions.  Almost  conclusive 
proof  of  this  essential  similarity  has  been  furnished,  on  the  one  hand, 
by  the  cures  which  are  obtained  in  Graves 's  disease  by  the  surgical 
removal  of  a  portion  of  the  hyperactive  thyroid  gland,  and,  on  the 
other,  in  the  almost  certain  demonstration  of  an  increased  amount  of 
iodothyrin  in  the  blood  of  patients  with  this  disease  (Reid  Hunt). 

This  author  has  discovered  in  the  varying  resistance  of  mice  toward  the 
highly  toxic  acetonitrile,  CH3CN,  an  exceedingly  delicate  test  for  iodothyrin. 
Feeding  of  minimal  doses  (1/10  mg.)  of  dried  thyroids  increases  this  resistance 
200  per  cent,  or  more.  Other  organic  substances,  including  normal  blood, 
possess  this  power  not  at  all  or  only  to  a  minimal  extent,  but  the  blood  of 
patients  with  Graves's  disease  does  possess  it. 

t These  undesirable  and  at  times  dangerous  effects  of  the  thera- 
tic  administration  of  thyroid,  particularly  its  power  of  increasing 
decomposition  of  proteids,  constitute  a  limitation  for  its  employ- 
ment which  should  not  be   disregarded.     For  therapeutic  employ- 
ment, as  a  rule,  dried  thyroid  substances  from  calves  or  the  powdered 
dried  extract,  or  thyroiodin  mixed  with  sugar   (1.0  gm.  —  1.0  gm. 
dried  thyroid),  are  employed. 

BIBLIOGRAPHY 

edl:    Die  innere  Sekretion,  Wien,  1910. 
v.  Cyon:  Die  Gefassdriisen,  Berlin,  1910. 
Hunt,  Reid:   Journ.  Am.  Med.  Assoc.,  1907. 


398  PHARMACOLOGY  OF  THE  METABOLISM 

Magnus-Levy:  v.  Noorden's  Hdb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2. 

Magnus-Levy:  Ztechr.  f.  klin.  Med.,   1897,  vol.  33. 

V.  Noorden:   Die  Zuckerkrankheit,  Berlin,   1907,  p.  54. 

v.  Noorden's  Handb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2. 

Pineles:  Sitz.-Ber.  d.  Akad.  d.  Wiss.,  1908,  vol.   117,  p.  3. 

Stookey,  L.  B.,  and  Vera  Gardner:  Proc.  Soc.  Exp.  Biol.  Med.,  1908. 


The  thyroid  is  not  the  only  gland  exerting  an  influence  on  metab- 
olism. The  hypophysis  and  the  genital  glands  through  their  inter- 
nal secretions  certainly  exert  an  influence  on  metabolism  and  growth, 
and  especially  on  the  development  of  the  bony  skeleton.  Hypoplasia 
of  the  genitals  causes  retarded  and  incomplete  calcification  of  the 
epiphyses  and  infantilism,  while  hypertrophy  of  the  hypophysis 
causes  stimulation  of  the  growth  of  bones,  acromegalia.  Both  of 
these  glands  appear  to  stand  in  an  intimate  relationship  with  each 
other  and  with  the  thyroid,  although  up  to  the  present  not  much  is 
exactly  known  about  this  (see  in  this  connection  A.  Frolich,  Biedl}. 

The  ancient  observation  that  castration  causes  an  increased  ac- 
cumulation of  fat  has  been  investigated  in  animals  by  Loewy  and 
Richter,  who  found  that  it  caused  a  retardation  of  metabolism  and 
of  oxidation,  which,  however,  according  to  Luthje,  does  not  occur  in 
all  cases.  That  these  effects,  when  they  do  occur,  are  due  to  the 
absence  of  the  internal  secretion  has  been  proven  by  the  fact  that 
the  administration  of  ovaries  or  testicles  can  again  stimulate  the 
diminished  metabolism,  while  in  normal  animals  their  administration 
produces  no  such  effect. 

That  the  suprarenals  also  exert  an  influence  on  the  general  metab- 
olism is  probable,  for  the  anomalies  of  metabolism  which  are  present 
in  Addison's  disease  are  best  explained  on  this  assumption.  These 
observations  have,  however,  not  led  to  any  therapeutically  well- 
grounded  or  practically  useful  results  for  treatment. 

Still  less  well  grounded  is  the  employment  of  numerous  other 
organotherapeutic  preparations,  such  as  those  obtained  from  the 
brain,  kidney,  and  other  organs,  which  under  various  names  are  ad- 
vertised with  unreserved  laudation. 

BIBLIOGRAPHY 

Biedl:   Die  innere  Sekretion,  Wien,  1910. 

Frohlich,  A.:  Wien.  klin.  Rundschau,   1901. 

Loewy  u.  Richter:   Dubois'  Arch.  f.   Physiol.,   1899,  Suppl. 

Liithje:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vols.  48  and  50. 

IODINE  AND  IODINE  COMPOUNDS 

While  iodine  must  also  be  numbered  among  those  substances 
especially  affecting  the  metabolism,  it  does  so  in  a  peculiar  and  limited 
degree  and  only  indirectly. 

LOCAL  ACTION. — "When  brought  in  contact  with  living  tissues  in 
concentrated  solution,  as  in  the  tincture  of  iodine  or  in  Lugol's  solu- 


IODINE  AND  IODIDES  39$ 

tion,  it  produces  in  them  substitution  products  and  oxidizes  them, 
just  as  it  does  all  labile  organic  substances.  Consequently  it  produces 
a  destructive  action  in  the  superficial  tissues  and  causes  a  more  or- 
less  marked  inflammatory  reaction.  That  portion  of  the  iodine  which 
is  not  fixed  at  the  point  of  application  is  absorbed  in  combination  with 
proteids  or  lipoids  or  in  the  form  of  salts  and  can  then  exert  its 
peculiar  systemic  actions. 

SYSTEMIC  ACTIONS. — These  general  actions  are  exerted  essentially 
by  all  readily  decomposed  substances  containing  iodine,  by  iodine 
itself,  and  by  the  iodides,  as  also  by  iodoform  or  iodized  fats,  etc. 
Consequently  the  therapeutic  indications  for  the  internal  administra- 
tion of  all  these  preparations  are  similar,  for  with  all  of  them  their 
effects  are  due  essentially  to  an  "  iodine  action."  This  is  especially 
true  for  the  iodides. 

The  iodide  of  potash  is  a  very  soluble  and  readily  absorbed  neu- 
tral salt  and  as  such  naturally  exerts  the  same  osmotic  "salt  action" 
as  does  sodium  chloride.  The  peculiar  actions,  however,  which  give 
to  it  a  special  therapeutic  value  not  possessed  by  the  other  halogen 
salts  are,  without  doubt,  to  be  attributed  to  the  iodine  which  is  set 
free  from  it  by  oxidation.* 

*  In  this  connection  reference  is  often  made  to  the  ion  actions  of  iodine, 
but  this  cannot  be  taken  for  granted  without  further  evidence.  A  solution  of 
KI  contains  iodine  ions  with  a  negative  charge,  just  as  a  solution  of  KC1  con- 
tains chlorine  ions  with  a  similar  charge.  However,  as  far  as  we  know,  these 
latter  exert  no  special  actions.  Of  them  we  know  only  that  they  are  necessary 
for  the  life  of  the  organism,  and  are  retained  by  it  with  great  tenacity,  even 
when  the  diet  contains  no  chlorine. 

Up  to  the  present  no  one  has  conducted  any  investigations  with  the 
object  of  finding  out  what  special  physiological  actions  are  exerted  by  the 
iodine  anions.  However,  they  cannot  be  very  important,  for  anion  actions  must, 
like  all  ion  actions,  start  abruptly  and  by  their  direct  actions  cause  noticeable 
disturbances.  However,  large  amounts  of  Nal  may  be  taken  by  mouth  or 
injected  subcutaneously  or  intravenously  without  causing  any  noticeable  direct 
disturbances,  the  toxic  action  developing,  if  at  all,  only  after  several  days,  and 
being,  therefore,  probably  the  result  of  secondary  chemical  changes  (Berg, 
Sgalitzer,  Stockman,  and  Charteris ) .  Barbera's  contradictory  results  obtained 
by  injecting  a  20  per  cent.  Nal  solution  into  the  veins  do  not  permit  of  any 
positive  deductions. 

That  action  which  we  know  as  "  iodine  action "  is,  however,  not  to  be 
attributed  to  the  iodine  anions  but  to  the  iodine  molecules,  for  it  is  these 
which  form  organic  combinations  with  various  organic  constituents  of  the 
body.  It  must  consequently  be  assumed  that  the  HI  is  set  free  from  KI  in  the 
organism  and  by  oxidation  is  transformed  into  I2  and  that  then  this  produces 
the  specific  actions,  perhaps  after  ionization  in  the  form  of  I  cations. 

If  HC1  were  as  readily  oxidizable,  NaCl  would  exert  Cl  actions.  HC1  is, 
however,  hardly  at  all  affected  by  oxidizing  agents,  while  HBr  is  readily  and 
HI  even  more  readily  affected  by  them,  and  consequently  specific  iodine  and 
bromine  actions  may  result  from  their  administration.  In  accordance  with  the 
law  of  mass  action,  a  small  portion  of  the  halogen  salts  is  always  hydrolytically 
dissociated  in  the  body  by  the  CO2  tension  which  is  always  present.  Free  HI 
and  HBr  are  very  unstable  and  undergo  oxidation  even  under  the  influence  of 
atmospheric  oxygen.  Binz  has  shown  that  KI  is  oxidized  by  living  protoplasm 
in  the  presence  of  CO,. 


400  PHARMACOLOGY  OF  THE  METABOLISM 

The  iodides  and  the  iodized  fats,  in  their  behavior,  stand  in  about 
the  same  relation  to  iodine  as  does  atoxyl  to  arsenious  acid  (see 
p.  535).  They  can,  like  atoxyl,  circulate  about  in  the  body  as  sub- 
stances which,  for  the  time  being,  are  indifferent  or  inactive  and, 
wherever  the  necessary  conditions  are  present,  give  off  free  iodine 
and -allow  it  to  act,  while  by  all  means  the  largest  part  of  the  admin- 
istered preparation  is  excreted  in  unaltered  form  or,  in  the  case  of 
iodized  fats,  deposited  in  various  indifferent  locations.  Substances 
which,  like  iodoform,  act  as  undecomposed  molecules  will  naturally 
•exert  actions  made  up  of  these  specific  actions  and  of  iodine  actions. 

Iodine  possesses  no  power  of  influencing  the  metabolism,  in  the 
usual  sense  in  which  this  phrase  is  used,  for  neither  experiments  on 
man  nor  on  animals  have  demonstrated  that  it  exerts  any  constant 
influence  on  the  transformation  of  energy  or  on  tissue  change.  Such 
action  is  indicated  only  by  a  series  of  clinical  observations,  such  as  the 
striking  emaciation  which  occurs  in  some,  but  by  no  means  all,  in- 
dividuals who,  for  a  long  time,  have  taken  iodine  or  KI  internally, 
and  the  atrophy  of  certain  glandular  organs,  especially  hyperplastic 
thyroids  and  the  mammary  glands,  which  may  also  occur  under  similar 
conditions.  This  general  emaciation  is,  however,  certainly  not  a 
direct  effect  of  the  "  iodine  action." 

Effects  on  Mucous  Membranes. — The  continuous  use  of  iodine 
preparations  very  often  causes  an  active  congestion  with  painful 
swelling  and  hypersecretion  in  the  mucous  membranes  of  the  nose, 
throat,  and  conjunctiva  and  also  of  the  pharynx  and  larynx,  while 
more  rarely  the  mucous  membranes  of  the  alimentary  canal  may  be 
affected,  especially  if  a  complicating  nephritis  interferes  with  its 
excretion  in  the  urine  (v.  Noorden). 

Effects  on  the  Skin. — In  a  similar  fashion  inflammatory  irritation 
of  the  skin  occurs,  with  acne  postules,  furuncles,  or  purpura,  all 
probably  the  effect  of  the  free  iodine  which  is  formed  by  oxidation 
from  the  iodine  excreted  in  the  glands  of  the  skin. 

Effects  on  Nutrition. — These  inflammations  of  the  mucous  mem- 
branes, especially  if  they  affect  the  stomach,  can  produce  a  marked 
disturbance  of  nutrition  and  may  occasionally  lead  to  emaciation. 
Ordinarily,  however,  even  after  the  use  of  large  amounts  of  KI  for 
months  at  a  time,  this  does  not  occur  except  in  certain  patients  with 
goitre. 

EFFECTS  ON  THE  THYROID. — In  such  individuals  the  administration 
of  iodine  in  any  form  is  followed,  often  after  a  few  small  doses,  by  the 
development  of  the  typical  clinical  picture  of  thyroidism  or  Graves 's 
disease,  with  the  rapid  loss  of  weight  and  strength  characteristic  | 
thereof   (Brewer,  Pineles).     It  may  consequently  be  concluded  that  i 
iodine  influences  the  metabolism  only  indirectly,  through  the  thyroid' 
glands,  and  to  an  appreciable  degree  only  in  case  the  thyroid  tissue 
is  hypertrophic  but  at  the  same  time  functionally  insufficient.     Such 


IODINE  AND  IODIDES  401 

conditions  of  the  thyroid  are  present  in  many  cases,  and  are  due  in 
all  probability  to  a  too  small  amount  of  iodine  in  the  glandular  tissue. 

It  is  well  known  that  the  physiological  activity  of  the  thyroid 
gland  is  determined  by  the  amount  of  thyroiodin  present  in  it  and 
that  the  poorer  it  is  in  iodine  the  less  active  it  is.  This  has  been 
proven  experimentally  by  Oswald,  Roos,  and  others,  and  in  a  very 
peculiar  fashion  by  Reid  Hunt  and  Atherton  Seidell.  Hoisted  states 
that  the  lack  of  a  sufficient  amount  of  active  iodothyrin  in  a  thyroid 
causes  the  hypertrophic  formation  of  glandular  tissues  which  are 
poor  in  colloids  and,  therefore,  chemically  and  functionally  insufficient. 
The  new-born  offspring  of  animals  deprived  of  their  thyroids  have 
markedly  hypertrophied  but  colloid-free  thyroids  (Hoisted,  Edmunds, 
A.  Kocher,  Reid  Hunt),  and  hyperplastic  human  or  animal  thyroids 
contain  little  or  no  iodine  (Oswald).  On  the  other  hand,  the  amounts 
of  thyroiodin  contained  in  the  thyroid  is  increased  by  the  admin- 
istration of  KI  or  other  iodine  preparations,  while  the  hyperplastic 
tissues  poor  in  colloids  atrophy  and  the  goitre  diminishes  in  size. 

From  all  this  it  can  hardly  be  doubted  that  iodine  changes  the 
functionally  weak  thyroid  tissue  which  is  poor  in  iodine  into  one  rich 
in  iodine  and  physiologically  active,  and  that  in  this  way  it  causes 
the  disappearance  of  the  superfluous  hyperplastic  glandular  tissues. 
This  conception  of  the  action  of  iodine  enables  us  to  understand 
the  pronounced  augmentation  of  the  catabolic  processes  in  the  whole 
body  which  sometimes,  particularly  in  cases  of  thyroidism,  occurs 
under  the  influence  of  iodine  medication  and  which  may  be  ac- 
companied by  temporary  febrile  manifestations.  From  the  foregoing 
it  is  clear  that  the  iodine  treatment  of  goitre,  introduced  by  Coindet 
in  1820,  rests  upon  a  physiological  basis. 

In  Scrofula. — Whether  or  not  the  benefits  resulting  from  the 
iodine  treatment  of  scrofulous  swelling  of  the  lymph-nodes  are  to  be 
explained  in  the  same  fashion  is  uncertain,  particularly  as  no  attempt 
has  been  made  to  determine  whether  or  not  the  scrofulous  diathesis 
of  many  (but  by  no  means  all)  tubercular  patients  is  dependent  on 
an  insufficiency  of  the  thyroid.  It  is  possible  that  in  these  cases  the 
favorable  results  are  due  to  a  direct  action  of  iodine  which  accelerates 
the  decomposition  or  destruction  of  the  pathological  tissues.  It  is 
also  possibly  of  significance  that  tubercular  tissue  absorbs  iodine 
more  strongly  than  normal  tissues  (Loeb  u.  Michaud). 

IN  SYPHILIS. — The  same  question  arises  in  connection  with  the 
symptomatic  curative  effects  of  the  iodides  in  syphilis.  There  is  no 
doubt  that  under  their  influence  there  occurs  a  rapid  degeneration 
and  disappearance  of  syphilitic  lesions,  especially  those  of  the  second 
and  third  stages,  but  a  definite  cure,  with  prevention  of  relapses,  is 
not  obtained  by  the  use  of  the  iodides.  A  definite  etiotropic  *  action 
cannot  be  attributed  to  it. 

*  An    etiotropic    action    is    an    action    directly    on    the    specific    organism 
ting  a  disease. 

26 


402  PHARMACOLOGY  OF  THE  METABOLISM 

IN  ATHEEOMA. — The  alleged  curative  action  of  iodine  in  atheroma 
is  quite  as  difficult  of  explanation.  The  functional  disturbances  oc- 
curring in  arteriosclerosis  which  are  due  to  the  faulty  blood  flow 
through  various  organs — e.g.,  in  cerebral  arteriosclerosis  and  angina 
pectoris — are  often  distinctly  benefited  by  KI  if  the  condition  is  not 
too  far  advanced.  According  to  Romberg,  this  is  due  to  this  drug's 
power  of  diminishing  the  alkalinity  of  the  blood,  which  change  per- 
mits of  a  more  ready  flow  of  blood  through  the  atheromatous  vessels 
(0.  Muller  u.  Inada).  How  this  effect  is  brought  aboujt  is  not  known 
(Adam).  The  alleged  vasodilating  action  of  KI  does  not  exist 
(Stockman  and  Charteris).  Thaussig's  observations  of  a  diminution 
of  the  hypertension  of  the  vessels  in  chronic  lead  poisoning,  which  he 
explained  as  due  to  a  vasodilating  action,  are  the  result  of  the  ac- 
celerated elimination  of  the  lead,  which  results  from  the  administra- 
tion of  iodides. 

The  beneficial  action  of  iodine  in  nervous  asthma  *  and  in  neuralgias 
is  altogether  incomprehensible,  but  its  beneficial  effect  in  chronic  lead 
and  mercury  poisoning  has  been  understood  since  it  was  shown  by 
Melsens  in  1844,  and  later  by  others,  that  the  elimination  of  these  two 
metals  is  distinctly  accelerated  by  the  administration  of  the  iodides. 

ADMINISTRATION. — For  the  various  indications  mentioned,  the 
iodides  of  potassium  and  of  sodium  are  administered  in  doses  rang- 
ing from  0.1  gm.  up  to  20.0  gm.  or  more  per  day,  or  the  newer  organic 
iodine  combinations,  such  as  iodipin  and  sajodin,  may  be  employed. 
The  former  is  a  combination  of  iodine  with  the  unsaturated  fatty 
acid  of  sesame  oil,  and  is  obtainable  in  two  strengths,  one  containing 
10  per  cent,  and  the  other  25  per  cent,  of  iodine.  Sajodin  is  a  cal- 
cium salt  of  a  fatty  acid  and  contains  20  per  cent,  of  iodine. 

BIBLIOGRAPHY 

Adam:  Ztschr.  f.  klin.  Med.,  1909,  vol.  68. 

Barbera:   Pfliiger's  Arch.,   1898,  vol.  68. 

Bins:  Virchow's  Arch.,    1874,   vol.   62. 

Breuer:  Wien.  klin.  Woch.,  1900,  Nos.  28  and  29,  here  literature. 

Edmunds:   Transact.  Pathol.  Soc.  London,  1900,  vol.  51,  p.  221. 

Halsted,  W.  8.:  Johns  Hopkins  Hosp.  Rep.,  1896,  vol.  I,  p.  373. 

Hunt,  Reid:   Journ.  of  Biologic  Chemistry,  1905. 

Hunt,  Reid:  Journ.  Am.  Med.  Assoc.,  1907. 

Hunt,  Reid,  and  Atherton  Seidall :  Labor.  Bull.  47,  Washington,  1900. 

Kern,  IL:   Diss.,   Tubingen,   1909. 

Kocher,  A.:  Mitt.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir. 

Loeb  u.   Michaud:  Biochem.  Ztschr.,   1907,   vol.   3. 

Muller,   O.,   u.   Inada:   Deut.  med.  Woch.,    1904. 

v.  Noorden:   Med.  Klinik.,  1908,  No.  1. 

Oswald:   Sammelref.  Biochem.  Zentralbl.,  1903. 

Pineles:  Wien.  klin.  Woch.,  1910,  No.  10. 

Sgalitzer:   Arch,  de  Pharmacodyn.,   1908. 

Stockman,  A.,  and  Charteris:  Brit.  Med.  Journ.,   1901,  here  literature. 

Stockman  and  Charteris:   Brit.  Med.  Journ.,  1901,  Nov. 

Thaussig:   Wien.  med.  Woch.,   1902,  No.  29. 

*  See    page    347. 


QUININE  403 

QUININE 

As  other  physiological  and  therapeutic  actions  of  quinine  will  be 
discussed  elsewhere  (pp.  470  and  527),  our  attention  will  here  be  di- 
rected only  to  the  direct  effects  of  this  drug  on  the  chemical  activities 
of  living  cells. 

The  antipyretic  action  of  calisaya  bark,  which  has  been  known 
ever  since  its  introduction  in  medicine,  and  the  improvement  in  the 
general  state  of  nutrition  of  run-down  individuals  which  results  from 
its  administration,  early  indicated  the  propriety  of  investigating  its 
effects  on  metabolic  phenomena.  Even  to-day  quinine  enjoys  a  reputa- 
tion as  a  tonic  or  means  of  improving  the  general  health. 

The  main  facts  concerning  the  actions  of  quinine  on  metabolism 
may  be  stated  briefly  as  follows.  Quinine  retards  all  the  vital  pro- 
cesses of  the  cells,  inhibiting  both  anabolic  and  catabolic  reactions.  In 
this  fashion,  even  small  doses  of  quinine  possess  the  power  of  sparing 
the  tissues  of  the  body,  but  when  its  effects  are  produced  in  the  highest 
degree  it  acts  as  a  general  destroyer  of  life,  and  causes  a  complete 
cessation  of  the  production  of  energy.  On  what  elementary  action 
this  depends  is  entirely  unknown.  We  know  only  that  it  may  be 
observed  in  almost  all  living  organisms,  in  the  lower  and  higher 
plants,  in  protozoa,  and  higher  up  in  the  scale  of  life.  Probably  it  is 
due  to  an  action  on  the  enzymes,  which  are,  as  it  were,  the  chemical 
tools  of  the  cells,  for  pure  enzyme  actions  are  weakened  or  entirely 
inhibited  by  quinine  (Laqueur),  which  possesses  the  power  of  in- 
hibiting oxidative  and  synthetic  reactions,  such  as  the  formation 
of  acid  in  the  blood,  the r^guaiac  reaction,  the  formation  of  hip- 
puric  acid  in  the  kidney,  the  phosphorescence  of  phosphorescent 
bacteria,  and  also  the  hydrolytic  and  catabolic  reactions  in  living  or 
surviving  organs. 

Consequently,  in  neither  the  lower  nor  the  higher  organisms  does 
quinine  cause  a  stimulation  of  vital  processes  or  of  regeneration  or 
stimulation  of  growth,  such  as  is  observed  under  the  influence  of 
thyroiodin. 

Even  the  apparent'  stimulation  of  muscular  power,  which  is  observed 
at  the  start  of  the  quinine  action,  is  not  the  result  of  any  true  increase  in 
the  production  of  energy,  although,  according  to  Santesson,  there  is  at  first 
an  augmentation  of  muscular  work,  which,  however,  is  quickly  followed  by 
a  correspondingly  more  rapid  exhaustion.  This  may  be  attributed  to  an 
inhibition  of  anabolic  processes,  as  is  done  in  connection  with  the  analogous 
action  of  alcohol  (Frohlich,  Lee).  Particularly  for  quinine  this  appears  to 
be  the  correct  explanation. 

All  exact  observations  agree  in  indicating  tJiat  the  proteid  metab- 
olism is  diminished  by  quinine,  the  nitrogen  balance  showing  that! 
less  nitrogenous  material  is  decomposed  when  quinine  is  given  than  \ 
is  normally  the  case.    This  is  true  in  health  and  in  fever,  when  food  is    \ 

:en  or  when  the  patient  is  fasting  (Loewi). 

As  under  normal  conditions  the  central  heat-regulating  mechan- 

.,  which  is  hardly  at  all  narcotized  by  quinine  (on  the  contrary, 


404  PHARMACOLOGY  OF  THE  METABOLISM 

it  is  perhaps  slightly  stimulated  at  the  start) ,  sees  to  it  that  the 
lessening  of  heat  production  is  compensated  for  by  diminished  heat 
loss  (Gottlieb)  or  by  an  increased  oxidation  of  non-nitrogenous  sub- 
stances, under  normal  conditions,  doses,  which  are  not  too  large,  do 
not  alter  the  total  transformation  of  energy  as  measured  by  con- 
sumption of  oxygen  and  excretion  of  carbon  dioxide,  nor,  as  a  rule, 
do  they  produce  any  alteration  in  the  body  temperature,  except  that 
occasionally  in  nervous  or  excitable  individuals  such  doses  may  at 
first  cause  a  slight  rise  in  temperature  (Fr.  Mutter). 

IN  FEVER. — If,  however,  the  heart-regulating  mechanism  is  in- 
adequate and  readily  fatigued,  as  is  the  case  in  infectious  fever,  the 
general  inhibitory  effect  of  quinine  on  the  chemical  processes  in  the 
body  causes  an  alteration  of  the  respiratory  exchange  of  gases,  due  to 
a  diminished  oxidation  of  all  substances,  both  nitrogenous  and  non- 
nitrogenous,  and  the  total  production  of  heat  is  diminished  (see 
Antipyretics,  p.  470).  The  direct  effect  of  quinine  on  the  central 
nervous  system,  which  may  cause  motor  restlessness  and  increase  of 
the  respiratory  volume,  and  its  effects  on  the  circulation,  namely,  ac- 
celeration of  the  heart-rate,  may  mask  this  fundamental  action  on 
metabolism. 

From  the  foregoing  it  may  be  seen  that  a  therapeutic  invigorating 
effect  on  the  metabolism,  leading  to  an  improvement  in  the  nutrition, 
is  not  to  be  expected  from  quinine,  for  it  certainly  does  not  favor 
the  formation  of  new  cell  material  and  probably  inhibits  it.  How- 
ever, it  may  exert  a  conservative  sparing  action,  particularly  in  such 
conditions  as  thyroidism,  infectious  fever,  etc.,  in  which  the  catabolic 
processes  are  abnormally  increased  as  a  result  of  pathological  stimuli 
and  in  which  there  is  a  rapid  loss  in  weight  and  strength.  Quinine 
may  be  said  to  retard  the  processes  not  only  of  life  J>ut  also 
of  dying. 

BIBLIOGRAPHY 

Frohlich:   Ztschr.  f.  allgem.  Physiol.,   1905,  vol.  5. 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,   1890,  vol.  26. 

Laqueur:  Arch.  f.  exp.  Path.  u.  Pharm.,  1906,  vol.  55,  here  literature. 

Lee,  F.  S.:  Am.  Journ.  of  Physiol.,  1907,  vol.  20,  p.  170. 

Loewi:   Hdb.  d.  Path.  d.  Stoff'w.,  1907,  vol.  2,  p.  792. 

Miiller,  Fr.:  Arch.  f.  klin.  Med.,   1893,  vol.  51. 

SUBSTANCES   INHIBITING  OXIDATION    ("Arsenic   Group"). 

LACK  OF  OXYGEN. — Augmentation  of  the  normal — apparently 
optimal — oxidation  of  the  blood  produces  no  effects  on  the  metabolism, 
but  diminution  thereof  produces  very  important  effects,  which,  in 
their  character  and  intensity,  vary  greatly,  with  the  more  or  less  in- 
sufficient supply  of  oxygen. 

A  slight  diminution  of  the  oxygen  tension  in  the  atmospheric  air, 
such  as  is  met  with  in  altitudes  of  about  1000  metres  above  the  sea 
level,  causes  an  increased  production  of  new  red  cells  and  probably 
also  of  other  tissues,  particularly  of  the  muscles,  for  with  the  same 


WATER  AND  SALT  ACTIONS  405 

intake  of  food  much  more  nitrogen  is  retained  than  corresponds  to 
the  newly  formed  haemoglobin  (Jaquet,  Jaquet  u.  Stakelin).  v. 
Wendt's  careful  experiments  on  himself  at  heights  of  between  3000 
and  4500  M.  showed  that,  in  addition  to  a  marked  retention  of  nitro- 
gen, there  is  a  retention  of  sulphur  and  iron  and  also  increased  as- 
similation of  phosphorus.  The  respiratory  exchange  of  gases  is  also 
increased  under  these  conditions,  a  fact  probably  of  much  importance 
in  connection  with  the  therapeutic  effects  of  the  high  altitudes. 

Very  insufficient  oxygen  supply,  on  the  other  hand,  such  as 
results  from  severe  hemorrhages,  anaemias,  and  dyspnoea,  leads  to  a 
marked  and  readily  recognizable  disintegration  and  degeneration  of 
tissues,  with  fatty  degeneration  and  abnormal  production  of  acids, 
and  to  a  retardation  of  synthetic  processes,  such  as  that  of  hippuric 
acid  in  the  kidney,  etc.,  and  finally  to  paralysis  of  all  functions. 

Just  as  a  moderate  insufficiency  in  the  oxygen  supply  causes  a 
favorable  stimulation  of  the  metabolism  and  the  retention  of  nutri- 
tive material,  and  as  a  more  pronounced  deficiency  causes  an  increased 
destruction  of  tissues,  a  number  of  chemical  agents  produce  the 
same  results.  It,  therefore,  is  not  improbable  that  their  action  in  the 
last  instance  depends  on  their  power  of  preventing  the  protoplasm 
from  utilizing  oxygen  (Loewi).  The  more  important  of  these  sub- 
stances are: 

(a)  Phosphorus. 

(b)  Arsenic  and  antimony  and  their  compounds. 

(c)  Iron  and  mercury. 

BIBLIOGRAPHY 

Frankel:  Virehow's  Arch.,  1876,  vol.  67. 

Jaquet:    Programm  Basel,  1904. 

Jaquet  u.  Stahelin:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46. 

Loewi:   Hdb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2,  p.  693. 

Prausnitz:    Sitz.-Ber.  Ges.  Morph.  u.  Physiol.,  Munchen,  1890. 

v.  Wendt:  Arch.  Physiol.  Inst.  d.  Univ.  Helsingfors,  1910,  p.  151. 

PHOSPHORUS 

It  is  only  the  chemically  active  yellow  phosphorus  which  possesses 
a  pharmacological  action,  and  it  appears  that  only  phosphorus  itself 
and  not  its  combinations  produce  these  effects,  for  there  are  no  known 
compounds  containing  it  which  produce  the  same  or  even  similar 
actions  (Schuchardt)  unless  nascent  phosphorus  is  set  free  from  them 
(Santesson). 

Phosphorus  is  very  slightly  soluble  in  water,  but  fairly  so  in 
many  organic  solvents  and  in  fats.  It  is  slowly  absorbed  from  the 
alimentary  canal,  and  its  characteristic  effects  develop  only  slowly 
and  gradually.  In  the  body  it  appears  to  be  hardly  oxidized  at  all 
tra-cellularly,  for  it  remains  unaltered  when  suspended  for  days 


406 


PHARMACOLOGY  OF  THE  METABOLISM 


in  arterial  blood  (H.  Meyer),  although  outside  of  the  body  it  is  very 
readily  oxidized  when  exposed  to  air. 

EFFECTS  ON  GENERAL  METABOLISM. — When  taken  in  very  small 
amounts  (%-l  mg.  per  diem  in  man)  phosphorus  stimulates  metabo- 
lism, causing  an  increased  growth  and  new  formation  of  tissues. 
While  exact  metabolism  experiments  on  children  or  young  animals 
have  never  been  made,  this  may  be  concluded  from  the  favorable 
effects  on  the  general  state  of  nutrition  observed  by  clinicians  and 
from  the  unusual  increase  in  the  weight  of  rhachitic  children  to  whom 
phosphorus  has  been  given  (Kassowitz,  Hagenbach,  Neumann}.  On 
the  other  hand,  we  possess  a  more  exact  knowledge  of  its  effects  on 
the  blood  and  on  the  bony  tissues. 

ON  BLOOD. — Among  the  first  effects  of  the  action  of  phosphorus 
in  man  is  an  increase  in  the  number  of  red  blood-cells  (Gowers, 
Thaussig),  and  even  after  large  toxic  doses  the  production  of  the 


FIG.  44. 


FIG.  45. 


Normal.  After  phosphorus. 

FIGS.  44,  45. — Heads  of  calves'  femur  (from  Wegner). 

red  cells  appears  to  be  increased  beyond  the  normal,  for  in  severely 
poisoned  mammals  their  number  is  not,  as  a  rule,  diminished,  al- 
though the  markedly  increased  production  of  bile  pigments  indi- 
cates an  increased  destruction  of  the  red  cells  *  (Stradelmann) . 

ON  BONE. — Phosphorus  influences  the  formation  of  bone  very 
markedly.  In  young  animals  the  growing  portion  of  the  epiphyses 
forms  a  compact  bone  instead  of  a  spongy  substance  and  the  osseous 
tissue  hypertrophies  at  the  expense  of  the  medulla  (Wegner}  (Figs. 
44  and  45).  These  effects  appear  to  be  similar  to  those  which  Schiff, 
after  dividing  the  nerves  of  the  leg,  observed  in  the  bones  of  the  leg 
and  foot  of  young  animals  as  the  result  of  the  continuous  congestion 
and  inflammatory  irritation  from  a  wound.  Phosphorus  thus  un- 
doubtedly stimulates  the  growth  of  bone,  or,  otherwise  expressed, 
causes  the  anabolic  processes  in  the  metabolism  of  bony  tissues  to 

*  In  the  chicken,  while  the  destruction  of  these  cells  is  at  first  so  great 
as  to  more  than  keep  pace  with  their  new  formation  and  their  number  ia 
markedly  diminished,  the  rapid  return  tc  normal  numbers  shows  that  the  new 
formation  of  the  red  cells  takes  place  very  rapidly  (Gowers,  Thaussig,  J.  Vogel). 


PHOSPHORUS  407 

preponderate  over  the  catabolic  ones.  By  chemical  analysis  Kochmann 
has  demonstrated  a  relative  increase  in  the  calcium  of  the  bones 
under  the  influence  of  chronic  phosphorus  poisoning.  This  increase 
amounts  to  a  change  of  from  21  per  cent,  to  25  per  cent,  of  the 
dried  residue. 

TOXICOLOGY. — The  harmful  effects  of  poisonous  doses  of  phosphorus 
manifests  itself  to  a  much  greater  degree  in  the  metabolism  of  the 
other  organs.  Morphologically  it  may  be  readily  recognized  ma- 
croscopically  in  the  liver,  heart,  and  kidneys,  and  to  some  extent 
in  the  diaphragm  and  the  other  muscles,  all  of  which  show  fatty 
degeneration  to  a  greater  or  less  extent.  In  the  liver  and  in  the  heart, 
this  fatty  degeneration  is  due  to  the  fact  that  fat  from  other  tissues 
is  deposited  in  them  (Loewi),  but  in  the  kidneys  it  appears  to  be  due 
to  the  fact  that  the  fat  and  lecithin  normally  present  in  them,  but, 
as  it  were,  hidden  or  combined,  is  set  free  and  becomes  visible  (Rubow, 
Mansfeld).  As  the  capillary  epithelial  cells  also  are  the  seat  of 
fatty  degeneration,  small  hemorrhages  readily  occur.  By  chemical 
analytical  methods  it  may  be  shown  that  phosphorus  causes  a  greatly 
increased  destruction  of  the  tissues,  with  marked  disturbance  of  the 
synthetic,  oxidative,  and  cleavage  reactions. 

The  consumption  of  oxygen  and  the  formation  of  C02  is  lessened. 
Less  fat  and  correspondingly  more  carbohydrates  and  proteids  are 
combusted,  which  latter,  however,  are  only  in  part  completely  broken 
down,  so  that  considerable  quantities  of  intermediary  metabolic  pro- 
ducts (amino  acids,  peptones,  lactic  acid,  and  many  others)  are 
present  in  the  blood.  In  agreement  with  this,  there  is  a  marked 
augmentation  of  the  autolytic  decomposition  of  proteid  in  the  livers 
of  animals  poisoned  by  phosphorus,  as  compared  with  normal  organs 
(Jacoby).  Moreover,  the  addition  of  phosphorus  to  the  perfused 
blood  strongly  inhibits  the  synthesis  of  hippuric  acid  in  the  isolated 
kidney  (Hauser). 

As  has  already  been  mentioned,  these  disturbances  of  metabolism 
agree  in  many  particulars  with  those  resulting  from  the  lack  of  oxy- 
gen, and  it  is  consequently  not  at  all  improbable  that  phosphorus 
renders  the  body  cells  less  capable  of  utilizing  oxygen  in  the  normal 
fashion. 

In  its  effects  on  function,  phosphorus  poisoning  manifests  itself 
by  a  progressive  diminution  in  the  functional  power  of  all  the  organs. 
The  cells  of  the  brain  become  incapable  of  performing  their  normal 
functions,  and  the  poisoned  individual  falls  into  a  state  of  apathy 
and  unconsciousness, — sometimes,  however,  into  a  state  of  delirium. 
The  movements  of  the  body  become  sluggish  and  feeble  and  the  heart 
and  the  vasomotor  apparatus  are  paralyzed.  If  large  amounts  of 
phosphorus  reach  the  blood  relatively  rapidly,  a  direct  paralysis  of 
the  heart  may  precede  all  other  symptoms  (H.  Meyer). 


408  PHARMACOLOGY  OF  THE  METABOLISM 

The  only  efficacious  treatment  of  phosphorus  poisoiving  is  the 
removal  of  the  poison  from  the  stomach  or  the  attempt  to  render  it 
harmless  by  securing  its  oxidation  in  the  alimentary  canal.  Copper 
sulphate  is  the  substance  best  adapted  for  this  purpose,  for  not  only 
does  it  cause  emesis,  but  by  its  reduction  the  phosphorus  is  oxidized 
to  phosphoric  acid,  and  at  the  same  time  any  phosphorus  still  un- 
changed combines  with  the  reduced  copper,  forming  an  insoluble 
copper  phosphide.  Permanganate  of  potash  also  energetically  oxi- 
dizes phosphorus,  but  ozonized  turpentine  which  is  recommended  as 
an  antidote  is  of  doubtful  value  [and  certainly  cannot  act  on  the  phos- 
phorus once  it  is  absorbed. — TB.]. 

THERAPEUTIC  USES. — After  phosphorus  was  discovered  to  be  an 
important  constituent  of  the  brain  and  nerves,  it  was  for  a  long  time 
used  with  alleged  great  benefit  in  the  treatment  of  different  nervous 
disturbances.  In  view  of  the  similar  employment  of  arsenic,  which, 
as  will  be  seen  below,  acts  in  an  entirely  analogous  fashion,  which 
employment  is  still  considered  as  justifiable,  these  older  claims  of  the 
value  of  phosphorus  in  such  conditions  should  not  be  dismissed  off- 
hand as  erroneous. 

Wegner's  experiments  have  furnished  a  scientifically  founded  jus- 
tification for  the  employment  of  phosphorus  in  osteomalacia  and  in 
rickets,  as  first  recommended  by  Kassowitz.  In  particular,  its  curative 
effect  in  rhachitic  children  is  not  to  be  disputed,  in  which  connection, 
it  should  be  noted,  that  not  only  does  formation  of  bone  become 
normal  again,  but  the  other  accompanying  symptoms  of  rickets  often 
disappear  with  surprising  rapidity.  All  the  same,  the  risks  in  pre- 
scribing phosphorus  are  not  slight,  for  the  rapidity  with  which  it  is 
absorbed  from  the  alimentary  canal  and,  consequently,  the  intensity  of 
its  effects,  appear  to  be  very  variable  and  impossible  to  estimate.  Doses 
of  1  mg.  of  phosphorus  daily  (two  teaspoonfuls  of  phosphorus  and 
cod-liver  oil  in  the  proportion  0.01: 100),  as  ordinarily  prescribed  by 
podiatrists,  are  almost  always  borne  without  harm,  but  such  doses 
taken  for  several  days  have  also  led  to  a  fatal  poisoning  (Nebelthau). 
The  attempt  should,  therefore,  be  made  to  abandon  the  therapeutic 
employment  of  phosphorus,  replacing  it  by  arsenic. 

BIBLIOGRAPHY 
Berg:  Diss.,  Dorpat,  18. 

Gowers,  by  Limbeck:   Grundriss  d.  Path.  d.  Blutes,  Jena,  1892. 
Hagenbach:   Zbl.  f.  Schweiz.  Aerzte,  1884. 
Hauser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36. 
Jacoby:   Ztschr.  f.  physiol.  Chemie,   1900,  vol.  30. 
Kassowitz:   Ztschr.  f.  klin.  Med.,  1884,  vol.  7. 
Kochmann:   Pfliiger's  Arch.,  1907,  vol.  119,  p.  417. 
Loewi:   V.  Noorden's  Handb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2,  p.  778. 
Mansfeld:  Zentralbl.  f.  Physiol.,  1907,  vol.  21,  p.  666. 
Meyer,  H.:  Arch.   f.  exp.  Path.  u.   Pharm.,   1881,  vol.   14. 
Nebelthau:  Miinchn.  med.  Woch.,  1901,  No.  34. 
Neumann:   Diss.,  Rostock,  1896. 
Rubow:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  52. 


ARSENIC  409> 

Santessen  u.  Malmgren:   Skand.  Arch.  f.  Physiol.,  1904,  vol.  15,  pp.  259  and  420. 

Schiff:   Compt.  rend.  Acad.  des  Sciences,  1854. 

Schuchardt:   Ztschr.  f.  rat.  Med.,  1856,  N.  F.,  vol.  7. 

Stadelmann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1887,  vol.  24. 

Thaussig:  Arch.  f.  exp.  Path.  u.  Pharm.,  1892,  vol.  30. 

Vogel,  J. :  Arch.  u.   Pharmacodyn.,   1902,  vol.   10. 

Wegner:  Virchow's  Arch.,  vol.  55,  1872. 

ARSENIC 

All  arsenical  combinations  which  are  capable  of  reacting  chemi- 
cally are  pharmacologically  active,  producing  effects  which  in  the  last 
instance  are  due  to  the  action  of  the  anion  As03  or  As04.  The 
organic  arsenical  compounds,  such  as  cacodylic  acid,  (CH3)2As02H, 
and  arseniuretted  hydrogen,  AsH3,  however,  first  produce  their  own 
peculiar  effects,  the  latter,  for  example,  being  very  powerfully 
haemolytic  and  in  this  fashion  capable  of  producing  fatal  results. 
With  the  continuous  administration  of  small  quantities  of  such  sub- 
stances these  characteristic  actions  are  hardly  apparent,  but  as  a 
result  of  the  formation  from  them  of  As03  (Heffter)  they  gradually 
cause  the  typical  effects  of  arsenic.  The  same  holds  true  for  atoxyl 
or  sodium  arsanilate  (IgersJieimer). 

There  is  no  evidence  that  either  arsenous  or  arsenic  acid  forms  any  com- 
bination with  any  of  the  constituents  of  the  protoplasm.  Their  solutions 
consequently,  for  the  time  being,  produce  no  visible  morphologic  changes  or 
functional  effects  in  the  nerves  or  other  tissues.  After  a  time,  however,  the 
poisoned  cell  dies  and  undergoes  post-mortem  changes.  It  is  not  known 
whether  this  is  due  to  a  catalytic  inhibition  of  vitally  important  chemical 
reactions,  or  is  due  to  a  chemical  reaction  between  arsenic  and  some  constituent 
of  the  protoplasm,  minimal  amounts  of  which  are  necessary  to  the  life  of  the 
cell.  As  ferments  are  not  markedly  influenced  by  arsenic,  the  catalytic  effect 
does  not,  a  priori,  seem  very  probable  (Sctuifer  u.  Bohm).  On  the  other  hand, 
the  possibility  of  a  specific  chemical  combination  between  arsenic  and  some 
constituent  of  protoplasm  is  rendered  improbable  by  Bertrand's  statement  that 
arsenic  is  an  integral  constituent  of  all  living  cells.  This  author  found  1/200 
nig.  of  arsenic  in  the  hen's  egg,  chiefly  in  the  yolk. 

ON  METABOLISM. — In  its  nature  the  action  of  arsenic  on  metabo- 
is  essentially  the  same  as  that  of  phosphorus.  In  very  small 
ounts  it  inhibits  oxidation  and  exerts  a  favorable  influence  on 
wth  and  assimilation,  causing  a  preponderance  of  assimilative 
esses  as  compared  with  those  of  dissimilation.  The  breeders  of 
als  have  long  recognized  this  effect,  and  the  so-called  arsenic 
ters  in  Steiermark  look  upon  this  as  definitely  established.  The 
.emist,  Kopp,  observed  that  he  gained  10  kilograms  in  weight  during 
the  course  of  two  months  in  which  he  was  working  with  arsenical 
substances  (Cries).  These  practical  experiences  have  been  confirmed 
by  exact  observations  on  animals,  in  which  the  growth  of  normal 
animals  was  compared  with  that  of  those  receiving  arsenic,  and  by 
making  exact  analyses  of  the  metabolism  under  the  influence  of 
arsenic  (Weiske).  In  Gies's  new-born  rabbits  of  the  same  litter,  to  one 
which  arsenic  had  been  administered  daily,  there  was  after  four 
ks  a  difference  in  weight  of  30  per  cent,  in  favor  of  the  animal 


410 


PHARMACOLOGY  OF  THE  METABOLISM 


fed  with  arsenic,  which  was  also  distinguished  from  its  control  by  a 
shining  pelt  and  a  more  abundant  supply  of  fat  in  the  subcutaneous 
tissues  and  in  the  peritoneal  cavity.  The  bones  of  the  arsenic  animal 
were  longer  and  thicker  in  the  cortex,  and  the  epiphyses  con- 
sisted of  thick,  compact  masses  of  bone  such  as  result  from  the  action 
of  phosphorus  (Fig.  46) .  Similar  observations  have  been  made  in  pigs 
and  fowls,  and,  furthermore,  the  offspring  of  animals  treated  with 
arsenic  were  much  stronger  than  those  of  the  normal  controls. 

On  Blood, — It  is  probable  also  that  the  formation  of  the  red 
cells  or  the  manufacture  of  haemoglobin  (Delpeusch)  is  stimulated 
by  arsenic,  but  this  has  not  been  denitely  proven  (Bettmann,  Stock- 
man; see  also  Pharmacology  of  the  Blood,  p.  435). 

Corresponding  to  this  improvement  of  the  assimilative  processes, 
the  nitrogen  balance  shows  a  retention  of  nitrogen,  indicating  in- 


FIG.  46. — Rabbit  femurs. 


creased  assimilation  of  proteid  (Weiske,  Imjanitoff).  Nothing  de- 
finite is  known  of  the  influence  exerted  on  the  total  metabolism  by 
small  doses  of  arsenic. 

It  has  been  claimed  that  arsenic  exerts  a  favorable  influence  on  the 
development  of  infusoria  (Sand),  higher  plants  (Zeller,  1826),  and  yeasts,  etc. 
( Schultze ) . 

Toxic  EFFECTS. — Contrasted  with  the  effects  of  small  doses  of 
arsenic  in  favoring  assimilation  and  facilitating  growth  and  regener- 
ation are  the  opposite  effects  of  large  doses  of  arsenic,  which  cause 
an  increased  destruction  of  the  tissues  of  the  body  and  an  inhibition 
of  the  functions  of  various  organs.  Among  these  effects  are  injury 
and  abnormal  destruction  of  the  red  cells  (Bettmann,  Stierlin,  Stock- 
man, Charteris)  and  as  a  result  of  this  the  development  of  jaundice, 
while  the  nitrogen  balance  indicates  an  increased  destruction  of 
proteids  (Gathgens,  Ko-ssel,  Imjanitoff]  and  at  the  same  time  the 
respiratory  exchange  of  gases  is  diminished  (Chittenden) .  Fatty 
degeneration  of  the  organs  also  ensues,  lactic  acid  appears  in  the 
blood  and  in  the  urine,  and  the  liver  loses  its  power  of  forming 
glycogen  (Naunyn,  Lucksinger,  Eonikoff}. 


ARSENIC  411 


Combination  of  Assimilative  and  Disintegrate  Actions. — Often, 
and  perhaps  as  a  rule,  both  of  these  effects  of  arsenic,  the  stimulation 
of  growth  and  the  destruction  of  the  tissues,  occur  at  the  same  time. 
Corresponding  to  the  momentary  resistance  and  vital  powers  of  the 
different  cells,  and  even  more  to  the  varying  distribution  of  the 
poison  in  the  different  parts  of  the  body,  in  one  place  the  favorable 
building-up  action  preponderates,  in  another  the  destructive,  while 
in  still  other  situations  no  appreciable  effect  occurs.* 

In  chronic  arsenical  poisoning  in  the  normal  body  those  cells  are 
especially  affected  which  perform  the  larger  portion  of  and  the  most 
complicated  of  the  chemical  reactions,  particularly  the  cells  of  the 
liver,  the  kidney,  the  capillaries,  and  the  blood.  Certain  pathological 
new  growths,  such  as  malignant  lymphoma,  syphilitic  gummata,  etc., 
appear  to  be  especially  susceptible  to  the  dissimilative  actions  of 
arsenic.  It  is  thus  possible  to  produce  such  effects  in  many  patho- 
logical growths  without  seriously  or  permanently  injuring  the  patient 
himself. 

ACUTE  POISONING. — Up  to  the  present  it  is  not  possible  to  ex- 
plain satisfactorily  the  therapeutic  effects  of  this  drug  by  our  knowl- 
edge of  the  direct  functional  disturbances  occurring  in  experimental 
acute  arsenical  poisoning.  In  poisoning  of  this  type,  frequently  but 
not  always,  the  symptomatic  picture  is  dominated  by  two  groups  of 
symptoms  which  develop  alongside  of  each  other,  one  group  being 
the  result  of  depression,  and,  in  more  severe  cases,  of  very  acute 
paralysis  of  the  central  nervous  system,  while  the  other  is  due  to 
the  severe  gastro-intestinal  lesions.  The  former  cause  extreme  las- 
situde, unconsciousness,  and  coma  and  failure  of  the  respiration  and 
circulation  from  paralysis  of  the  respiratory  and  vasomotor  centres, 
while  the  lesions  in  the  alimentary  canal,  which  also  develop  after 
subcutaneous  or  intravenous  administration,  cause  violent  pains, 
vomiting,  and  choleraic  diarrhoea. 

There  appears  to  be  a  close  connection  between  the  gastro-intestinal 

turbances  and  the  disturbance  of  the  circulation  which  develops 
at  the  same  time  and  manifests  itself  by  a  pronounced  fall  in  the 
arterial  blood-pressure  and  a  small,  weak  pulse.  Experimental  an- 
alysis of  the  circulatory  failure  has  shown  that,  in  addition  to  a  weak- 
ening of  the  heart  muscle,  there  is  a  diminution  of  the  excitability 
of  the  vasomotor  centres,  and  that  finally  the  intestinal  vessels  no 
longer  react  to  electric  stimulation  of  the  splanchnic  nerves  in  the 
periphery.  The  contractile  elements  of  the  capillaries  of  the  portal 
system  are  completely  paralyzed,  so  that  the  blood  accumulates  and 
stagnates  in  them  and  their  veins  (Pistorius,  Heubner}.  As  a  result 
of  this  capillary  paralysis,  there  is  a  profuse  transudation  of  serous 

*  The  difference  in  effect  is  especially  well  evidenced  in  plants,  those  con- 
taining chlorophyll  being  especially  susceptible  to  arsenic;  of  those  containing 
none,  the  yeast  fungus  and  many  bacteria  are  very  insusceptible,  while  the 
mycoderma  oidium  is  entirely  immune. 


412  PHARMACOLOGY  OF  THE  METABOLISM 

fluid  into  the  intestines,  whose  epithelium,  being  here  and  there  fattily 
degenerated,  is  raised  up,  and  with  the  masses  of  the  exudate  may 
form  a  pseudo-membrane.  A  profuse  watery  diarrhoea  results,  the 
stools  containing  shreds  of  mucous  membrane  and  at  times  blood. 

As  the  mucous  membrane  of  the  intestine  is  directly  injured  as  a  result 
of  the  stasis,  and  probably  in  part  also  by  the  arsenic  excreted  through  it,  it  is 
not  able  to  resist  the  attacks  of  the  bacteria  to  which  it  is  constantly  exposed, 
and  parts  of  it  succumb  to  a  rapid  destruction,  so  that  ulcers  may  be  formed 
(toxic  autolysis).  Necroses  therefore  are  likely  to  be  more  extensive  and 
severe  in  the  large  intestine  than  in  the  small  intestine,  which  contains 
relatively  few  bacteria  (Cloetta). 

Among  the  less  direct  effects  are  pronounced  anasmia  of  all  the 
other  organs,  anuria,  asphyxia  of  the  central  nervous  system,  con- 
vulsions, and  paralysis. 

The  central  paralysis  caused  by  arsenic  is,  however,  not  due  to  this 
interference  with  its  blood  supply,  but  to  a  direct  toxic  action  of  the  drug. 
This  is  shown  by  the  results  of  experiments  on  the  frog,  whose  central  nervous 
system  is  rapidly  paralyzed  from  below  upward  when  poisoned  by  arsenic, 
although  it  can  support  for  hours  an  anaemia — for  example,  one  caused  by  a 
standstill  of  the  heart  or  by  replacing  the  blood  with  normal  NaCl  solution. 

The  blood  and  lymph  capillaries  of  the  splanchnic  system  are  more 
susceptible  to  arsenical  poisoning  than  those  in  any  other  portion 
of  the  body,  and  in  very  acute  poisonings  are  almost  the  only  ones 
visibly  affected. 

In  chronic  poisoning,  however,  or  when  the  drug  is  used  medicin- 
ally for  a  considerable  period  of  time,  capillary  paralysis  and  de- 
generation also  occur,  and  often  in  fact  chiefly  in  other  mucous  mem- 
branes and  in  the  skin.  This  accounts  for  the  conjunctivitis  with 
oedema  of  the  lids  and  for  the  angina,  rhinitis,  etc.,  and  for  the  de- 
velopment of  exanthemata  resembling  measles  or  scarlatina,  as  well 
as  of  herpes  zoster,  all  of  which  are  not  infrequently  observed  under 
these  conditions.  Finally,  arsenical  melanosis,  a  brown  pigmentation 
of  the  skin,  resulting  from  chronic  inflammation,  may  develop  and 
last  for  months  or  years.  The  lesions  of  the  peripheral  nerves,  poly- 
neuritis,  which  may  develop  in  chronic  arsenical  poisoning,  are 
probably  also  to  be  attributed  to  a  primary  toxic  action  on  the 
capillaries  of  the  nerves. 

THERAPEUTIC  ACTIONS. — We  have  no  exact  knowledge  of  the  extent 
to  which  curative  effects  of  arsenic  are  due  to  such  actions  on  the 
capillaries  in  the  skin,  the  nervous  system,  and  elsewhere.  It  is 
possible  that  this  is  of  moment  in  the  healing  of  the  lesions  of  psoriasis. 
For  the  present,  however,  we  have  no  explanation  for  the  clinically 
well-established  value  of  arsenic  as  a  means  of  relieving  neuralgias 
and  many  neuroses,  such  as  chorea  and  asthma  nervosa. 

On  the  other  hand,  the  already  mentioned  primary  action  of 
As03  on  metabolism,  which,  according  to  the  individual  susceptibility 


WATER  AND  SALT  ACTIONS  413 

or  accessibility  of  the  cells  of  the  different  organs,  results  in  an  ac- 
celeration of  the  growth  or  death  and  destruction  of  the  cells,  may 
be  considered  as  a  theoretical  justication  for  prescribing  arsenic  in 
those  cases  in  which  the  indication  is  either  to  improve  the  nutrition 
and  growth  of  organs  which  are  too  feebly  developed  or  to  cause 
an  absorption  or  destruction  of  pathological  new  growths  or  the 
destructions  of  parasities.  Such  are  a  poor  state  of  general  nutrition, 
cachexia,  chlorosis,  pathological  disturbances  of  the  growth  of  bones, 
such  as  ricketts  or  osteomalacia,  in  which  last  arsenic  should  be  sub- 
stituted for  phosphorus,  the  action  of  which  it  is  so  much  more  difficult 
to  estimate.  Malignant  lymphoma,  pseudoleukasmia,  syphilis,  and  some 
parasitic  diseases  are  examples  of  the  type  of  case  in  which  the 
destructive  effects  are  desired. 

The  ordinary  doses  range  between  0.5  and  5.0  mg.  of  arsenic 
trioxide  (arsenious  acid),  which  may  be  administered  in  different 
preparations  or  in  mineral  waters  containing  arsenic. 

In  conclusion,  the  use  of  arsenic  pastes  to  cause  a  local  destruction 
or  death  of  tissues  should  be  mentioned.  Their  use  is  now  almost 
entirely  limited  to  their  employment  in  dentistry  for  the  purpose  of 
killing  the  nerves  in  the  roots  of  teeth,  but  formerly  they  were  widely 
used  as  a  means  of  destroying  superficial  epitheliomata. 

THE  ORGANIC  ARSENICAL  COMPOUNDS  have  been  found  to  be 
especially  adapted  to  produce  an  etiotropic  effect  on  parasites  with 
the  greatest  degree  of  certainty  and  without  essentially  injuring  the 
patient.  Among  such  preparations  atoxyl  and  salvarsan  (see  p.  535  ff.) 
are  especially  to  be  mentioned. 

Excretion  and  Fat  in  the  Body. — Arsenious  acid  is  excreted  from 
the  body  but  slowly,  and  it  would  appear  that  it  is  never  completely 
excreted.  The  lacteal  glands  are  among  the  organs  through  which 
this  excretion  takes  place,  but  after  administration  by  mouth  a  con- 
siderable amount  is  excreted  in  the  faeces,  a  smaller  part,  4  to  14 
per  cent.,  appearing  in  the  urine,  while  a  very  important  remainder, 
varying  from  20  to  80  per  cent.,  is  never  excreted  in  any  recognizable 
manner  (Hausmann,  Heffter).  After  subcutaneous  injection,  the 
same  holds  good,  except  that  now  the  larger  portion,  from  10  to  19 
per  cent.,  is  excreted  in  the  urine,  and  the  smaller  part,  from  3  to  4 
per  cent.,  in  the  fasces.  A  small  part  of  the  arsenic  is  absorbed  by 
and  retained  in  the  hairs,  and  leaves  the  body  in  hairs  and  other 
epidermoid  structures  as  they  are  cast  off.  "Whether  arsenic  remains 
permanently  in  the  body  and  in  what  form  or  place  (perhaps  in  the 
bones?)  is  not  known. 

Tolerance. — If  at  first  the  arsenic  be  carefully  administered  in 
small  doses,  tolerance  increases  to  such  an  extent  that  after  a  time 
doses  may  be  borne  without  injury  which  would  otherwise  be  certain 
to  cause  illness,  and  perhaps  even  as  much  as  3  or  4  times  the  usual 
lethal  dose  may  be  taken  without  harm.  This  has  been  observed 


414  PHARMACOLOGY  OF  THE  METABOLISM 

in  the  arsenic  eaters  of  the  Steiermark  and  has  been  confirmed  by  ex- 
periments on  animals  (Hausmann} .  [Clinical  experience  also  indi- 
cates that  a  marked  degree  of  tolerance  is  readily  established. — TR.] 
Under  these  conditions  the  organism  apparently  retains  larger 
amounts  of  the  drug  and  possibly  acquires  a  greater  ability  to  form 
nontoxic  organic  combinations  of  arsenic.  Cloetta,  however,  claims 
that  the  tolerance  is  due  to  the  fact  that  the  absorption  of  arsenic 
from  the  alimentary  canal  decreases,  the  mucous  membrane  of  the 
intestines  becoming  resistant  and  impermeable  to  it.  Whether  at  the 
same  time  a  general  habituation  of  the  cells  to  the  specific  action  of 
arsenic  also  takes  place  has  not  been  sufficiently  investigated.  With 
yeast-cells  this  appears  to  be  the  case,  but  in  animals  it  is  very 
doubtful.  Hausmann  found  only  that  the  mucous  membranes  of 
dogs  which  were  accustomed  to  take  arsenic  were  distinctly  more 
resistant  to  the  caustic  action  of  As203  than  were  those  of  normal 
animals.  Cloetta' s  dogs,  which  had  become  habituated  to  arsenic, 
died  a  few  hours  after  the  subcutaneous  injection  of  only  one- 
sixtieth  of  the  dose  which  for  months  past  had  been  taken  by  mouth 
without  injury. 

BIBLIOGRAPHY 

Bettmann:      1897.     Cited  by  Stockman  and  Charteris. 

Chittenden:   Cited  by  Maly,  1887,  p.  17. 

Cloetta:  Arch.  f.  exp.  Path.  u.  Pharm.,   1906,  vol.  54. 

Delpeusch:  ThSse  de  Paris,  1880. 

Gathgens:  Zbl.  f.  med.  Wiss.,  1875  and  1876. 

Gies:  Arch.  f.  exp.  Path.  u.  Pharm.,  1877,  vol.  8. 

Hausmann:   Pfliiger's  Arch.,  1906,  vol.  113. 

Heifter:  Arch,   intern,   de   Pharmacodyn.,    1905,   vol.    15. 

Hetfter:     Arch.  f.  exp.  Path.  u.  Pharm.,   1901,  vol.  46,  p.  230. 

Heubner:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56,  p.  370. 

Igersheimer  u.  Rothmann:   Ztschr.  f.  Phys.  Chemie,  1909,  vol.  59,  p.  256. 

Imjanitoff:   Cited  by  Maly,   1901,  p.  751. 

Konikoff:  Cited  by  Maly,  1876. 

Kossel:  Arch.  f.  exp.  Path.  u.  Pharm.,   1876,  vol.  5. 

Luchsinger:  Diss.,   1875. 

Naunyn:   Ziemssen's  Handb.,  vol.  15,  p.  350. 

Onaka:  Ztschr.  f.  phys.  Chem.,  1911,  vol.  70,  p.  433. 

Pistorius:  Arch.  f.  exp.  Path.  u.  Pharm.,  1883,  vol.  16. 

Schafer  u.  Bohm:  Verh.  d.  Wiirzb.  Ges.,  1872,  vol.  3. 

Stierlin:   1889.     Cited  by  Stockman  and  Charteris. 

Stockman  and  Charteris,   1903. 

VVeiske:  Journ.  f.  Landwirtschaft,    1875. 

ANTIMONY  AND   ITS   COMPOUNDS 

In  many  regions  antimonial  preparations  are,  like  arsenic,  em- 
ployed to  improve  the  nutrition  of  cattle  and  to  fatten  them.  As  a 
matter  of  fact,  the  effects  on  the  animal  organism  are  qualitatively 
the  same  as  those  of  arsenic,  and  differ  from  them  only  in  degree 
and  in  the  order  in  which  the  different  effects  occur.  The  same  isi 
true  in  regard  to  the  effects  on  metabolism.  In  practice  tartar  emetic 
has  been  used  in  the  same  fashion  as  arsenic  in  the  treatment  of 


IRON  AND  MERCURY  415 

psoriasis,  but  at  present  it  is  used  almost  exclusively  as  an  emetic. 
[Antimonial  preparations  were  formerly  much  used,  especially  in  the 
treatment  of  pneumonia,  to  slow  the  heart  and  lower  the  blood- 
pressure.  These  effects  appear  to  be  due  to  a  direct  depressing  toxie 
action  on  the  heart  muscle  and  to  an  action  on  the  blood-vessels 
similar  to  that  of  arsenic.  At  the  present  time  no  one  would  think 
of  using  these  drugs  for  such  purposes. — TR.]. 

BIBLIOGRAPHY 
Gathgens:  Zbl.  f.  d.  med.  Wiss.,  1876. 

tlRON 
Iron  and  its  compounds  may  also  be  looked  upon  as  exerting  a 
jet  specific  action  on  the  metabolism.     This  is  evidenced  by  their 
well-established  influence  on  the  formation  of  the  blood-cells  (see  p. 
440),  as  also   by  their  "tonic  action"  in  improving  the  general  nutri- 
tion, which,  although  by  no  means  definitely  demonstrated,  is  generally 
accepted  by  clinicians.    Moreover,  its  importance  as  an  element  essential 
to  all  plant  life  has  been  certainly  established  (Molisch},  while  Fromme 
has  found  that  it  favorably  influences  the  growth  of  bacteria.    Iron  also 
appears  to  play  a  role  in  the  activity  of  many  enzymes  (Sacharoff} . 

The  toxic  actions  of  iron  resemble  those  of  arsenic  and  antimony 
[but,  owing  to  its  slow  absorption,  they  never  occur  except  under 
laboratory  conditions. — TR.]. 

BIBLIOGRAPHY 

Fromme:  Diss.,  Marburg,  1891. 

Molisch:  Sitz.-Ber.  d.  k.  Akad.  d.  Wiss.  zu  Wien,   1894,  vol.   103. 

Sacharoff:    Jena,   1902. 

MERCURY 

It  has  long  been  known  that  patients  undergoing  a  prolonged  treat- 
ment with  mercury  often  gain  markedly  in  weight  (Liegeois),  and 
this  has  been  confirmed  by  experiments  on  animals,  in  which,  when 
very  small  doses  of  HgCl2  are  taken  for  a  long  time,  growth  is 
stimulated  and  the  body  weight  increased,  while  the  red  blood-cells 
increase  in  number  (for  lit.  see  Schlesinger) ,  even  though  in  an  ex- 
periment of  but  a  few  days'  duration  the  metabolic  balances  may 
furnish  no  evidence  of  such  effects. 

In  chronic  mercurial  poisoning  or  mercurial  cachexia,  we  see  the 
results  of  directly  contrary  actions, — namely,  acceleration  of  cell 
decay  and  inhibition  of  oxidation.  The  severe  nephritis,  which  de- 
velops almost  immediately  in  acute  mercurial  poisoning,  makes  it 
impossible  to  demonstrate  these  effects  by  determination  of  the  nitro- 
gen balance  as  has  been  done  for  As203.  However,  the  disappearance 
of  glycogen,  the  appearance  of  lactic  acid,  and  the  fatty  infiltration 
of  the  various  organs  indicate  that  qualitatively  the  toxic  action  is 


416  PHARMACOLOGY  OF  THE  METABOLISM 

essentially  similar  to  that  of  arsenic.  Mercurial  poisoning,  however, 
is  differentiated  from  the  latter  by  a  more  extensive  destruction  of 
the  erythrocytes  (Kaufmann)  and  by  changes  in  the  bones,  which 
become  poorer  in  lime  salts  and  thinner  and  more  brittle  (Prevost, 
Heilborn). 

Presumably  this  power  of  causing  tissue  degeneration  is  of  essen- 
tial importance  in  connection  with  the  employment  of  mercury  for 
the  purpose  of  causing  the  rapid  disappearance  of  syphilitic  erup- 
tions and  new  growths,  which  even  when  untreated  show  but  slight 
tendency  to  persistence.  It  has  been  shown  by  Justus  that  mercury 
reaches  the  capillaries  and  permeates  the  cells  of  these  lesions.  Still 
more  important,  however,  just  as  is  the  case  with  arsenical  compounds, 
is  the  etiotropic  action  on  the  Spirochgeta  pallida  (see  p.  540). 

Chronic  mercurial  poisoning  may  develop  and  lead  to  most  dis- 
astrous results  in  patients  undergoing  long-continued  mercurial  treat- 
ment or  in  individuals  working  in  certain  occupations  in  which  they 
are  exposed  to  the  danger  of  continual  absorption  of  mercury. 
Among  such  are  workers  in  quicksilver  mines,  in  mirror  and  ther- 
mometer factories,  etc. 

As  a  rule,  the  first  symptoms  of  chronic  poisoning  are  similar 
to  those  of  subacute  poisoning, — salivation,  stomatitis,  and  diarrhoea, 
to  which  are  superadded  very  characteristic  disturbances  of  the  cen- 
tral nervous  system.  A  condition  of  extreme  psychic  irritability, 
erethismus  mercurialis,  develops,  and  the  patients  become  anxious  and 
readily  embarrassed  or  frightened,  and  not  infrequently  active  mania 
may  develop.  A  mercurial  tremor  of  the  muscles  of  the  face  and 
extremities  develops,  at  first  occurring  only  during  voluntary  move- 
ments but  later  occurring  spontaneously  and  even  during  sleep. 
Finally,  clonic  convulsions  may  occur,  which  are  occasionally  ac- 
companied by  epileptiform  attacks  and  hallucinations  of  hypo- 
chondriasis  or  other  psychic  disturbances.  At  the  same  time  the 
nutrition  is  rapidly  impaired  and  pronounced  cachexia  develops,  and 
the  patient  becomes  anaemic  and  the  skin  and  muscles  flabby.  Not 
infrequently  the  jaw-bones  undergo  necrosis  similar  to  that  occurring 
in  phosphorus  poisoning. 

Intercurrent  diseases,  most  frequently  phthisis,  usually  cause  death 
when  such  conditions  have  developed.  If,  however,  the  patients  are 
not  too  seriously  poisoned  and  the  absorption  of  the  mercury  is 
checked,  by  stopping  its  administration  or  by  removing  the  patients 
from  the  mercurial  environment,  recovery  may  ensue  after  a  time, 
but  in  some  cases  certain  of  the  symptoms  may  persist  indefinitely 
(Kussmaul) . 

BIBLIOGRAPHY 

Heilborn:   Arch.  f.  exp.  Path.  u.  Pharm.,  1878.  vol.  8. 

Justus:   Arch.  f.  Derm.  u.  Syph.,  1901,  vol.  57. 

Kaufmann,  C. :   Die  sublimatintoxikation,  1888,  here  literature. 


CERTAIN  PHASES  OF  METABOLISM  417 

Kussmaul:  Untersuch.  lib.   d.  konstitution.  Mercurial ismus,   1861. 

Liegeois:  Gaz.  des  HOpitaux,   1869. 

Prevost:  Rev.  Med.  de  la  Suisse   rom.,   1882. 

Schlesinger:  Arch.  f.  exp.  Path.  u.  Pharm.,  1881,  vol.  13. 

LECITHIN 

In  this  connection  it  should  be  mentioned  that,  according  to 
Danilewsky,  frogs'  eggs  and  larvae  grow  and  develop  more  rapidly 
under  the  influence  of  lecithin  than  under  normal  conditions.  Cron- 
heim  and  Muller  assert  that  the  addition  of  lecithin  to  the  diet  of 
nurslings  is  followed  by  an  increased  assimilation  of  proteid  (also 
Gilbert  et  Fournier,  Slowtzoff). 

[Lest  such  statement  should  lead  to  an  exaggerated  idea  of  the 
value  of  the  lecithin  preparations,  which  are  so  widely  exploited  to 
the  profession,  the  reader  is  reminded  that  lecithin  is  a  constituent  of 
many  articles  in  our  usual  diet.  The  yolk  of  eggs,  for  example,  con- 
tains it  in  large  amounts. — TR.]. 

Cronheim  u.  Miiller:  Jahrb.  f.  Kinderheilk.,  1900,  vol.  2,  Sept. 
Danilewsky:   La  Sem.  Medicale,   1896,  No.  2. 
Danilewsky:   Fortschr.  d.  Med.,   1896,  No.  20. 
Gilbert  et  Fournier:  Progr.  medic.,  1901,  p.  129. 
Slowtzoff :   Beitr.  z.  chem.  Phys.  u.  Path.,  1906,  vol.  8,  p.  370. 

DRUGS  AFFECTING  CERTAIN  PHASES  OF  METABOLISM 

Thus  far  in  this  chapter  the  total  metabolism  has  been  discussed 
as  if  it  were  something  without  complexity,  serving,  as  it  were,  as  a 
general  expression  of  the  intensity  of  vital  processes  and  growth 
of  the  cells  of  the  body.  Such  a  summary  consideration  is,  however, 
no  more  and  no  less  justifiable  than  is,  for  example,  the  general  dis- 
cussion of  the  narcosis  of  living  cells.  The  essentialities  of  such  a 
phenomenon  may  be  observed,  it  is  true,  on  all,  cells,  whether  differ- 
entiated or  not,  and  may  be  considered  from  a  general  standpoint,  but 

re  exist  in  individual  instances  the  greatest  quantitative  differences 

these  effects,  corresponding  to  the  chemical  and  functional  differen- 
tiation of  the  different  cells.  The  same  holds  true  for  the  actions  of 
the  ''metabolic  drugs"  thus  far  discussed,  and  already  we  have 
noted  certain  striking  differences  in  the  degree  and  manner  in  which 
the  metabolism  of  different  cells  may  be  affected  by  different  drugs. 
Such,  for  example,  are  the  especially  predominant  actions  exerted  on 
the  bones  by  such  drugs  as  phosphorus,  antimony,  and  arsenic,  or  by 
such  internal  secretions  as  those  of  the  thyroid,  the  hypophysis,  and 
the  sexual  glands,  while  the  marked  influence  exerted  by  iron  on  the 
haematopoietic  organs  is  another  instance  of  such  specialized  action. 

However,  not  only  do  the  different  types  of  cells  exhibit  such 

differences  in  their  reactions  to  these  various  "  metabolic  drugs," 

but  the   different  integral   constituents   of  the   cells   also  manifest 

similar  differences  in  their  reaction  to  them.    It  is,  therefore,  necessary 

27 


418  PHARMACOLOGY  OF  THE  METABOLISM 

in  this  connection  to  consider  more  or  less  individually  not  only  the 
cell  as  a  whole,  but  also  the  organic  energy-producing  complex,  as 
well  as  the  catalyzers  of  the  cells,  their  enzymes,  their  nuclear  sub- 
stances, and  their  mineral  constituents. 

However,  right  here  we  find  our  knowledge  especially  deficient, 
for,  with  the  exception  of  a  slight  knowledge  of  the  mineral  metabo- 
lism of  the  cells,  such,  for  example,  as  the  action  of  Hg  and  of 
acidosis  in  removing  Ca  from  the  body  and  that  of  P  and  As  in 
causing  its  assimilation  (Fait a),  we  know  almost  nothing  about  any 
regular  orderly  influencing  of  the  special  phases  of  metabolism  by 
pharmacological  agents. 

CARBOHYDRATE  METABOLISM 

DIABETES  MELLITUS. — One  of  the  most  important  of  such  dis- 
turbances of  one  phase  of  the  metabolism  is  that  which  occasions  a 
faulty  utilization  of  the  carbohydrates,  whether  this  be  due  to  the 
fact  that  the  carbohydrates  taken  in  the  food  or  those  formed  from 
proteid  are  not  stored  up  and  retained  in  the  form  of  glycogen  and 
fat,  or  results  from  the  inability  of  the  actively  functioning  body  cells 
to  assimilate  and  utilize  them  as  sources  of  energy.  In  either  case  the 
amount  of  the  carbohydrates  (usually  glucose)  present  in  the  blood 
increases  above  the  limit  which  can  be  kept  back  by  the  kidney,  and 
consequently  it  is  excreted  in  the  urine  without  being  utilized  by  the 
body.  A  discussion  of  the  possible  causes  of  these  hyperglycsemic 
forms  of  diabetes  is  of  no  value  for  our  present  purposes,  for  it  has 
not  yet  been  possible  to  obtain  any  satisfactory  and  proven  explana- 
tion of  the  manner  in  which  these  conditions  may  be  influenced 
by  drugs.  Empirically  it  has  been  definitely  established  that  the  ad- 
ministration of  certain  drugs,  alkalies,  opium  in  large  doses,  jambul, 
and  salicylic  acid,  lessens  the  excretion  of  sugar  (Kaufmann) . 

According  to  J.  Rudisch,  the  tolerance  for  carbohydrates  is  increased  by 
atropine  sulphate,  as  also  by  larger  doses  of  the  less  poisonous  atropine- 
methylium  bromide  (8  mg.  t.  i.  d.).  Cavazzani  and  Soldaini  conclude  from  their 
experiments  that  atropine  paralyzes  those  nerves  in  the  liver  which  excite  the 
formation  of  glycogen. 

Toxic  GLYCOSURIAS. — In  poisoning  due  to  many  different  agents, 
hyperglycgemic  glycosuria  occurs  as  a  temporary  symptom.  Among 
these  are  all  poisonings  causing  asphyxia,  whether  due  to  depression 
of  the  respiratory  centre,  such  as  is  caused  by  narcotics,  or  to  paraly- 
sis of  the  respiratory  muscles,  such  as  may  be  caused  by  curare,  or 
to  interference  with  the  function  of  the  haemoglobin  of  supplying  oxy- 
gen to  the  tissues,  which  may  result  from  the  actions  of  Wood 
poisons,  particularly  carbon  monoxide.  That  the  asphyxia  is  the 
cause  of  all  these  glycosurias  is  proven  by  the  fact  that  in  these 
intoxications  the  glycosuria  may  be  prevented  by  the  free  admin- 
istration of  oxygen  wherever  this  may  still  be  utilized,  which-  evidently 


CARBOHYDRATE  METABOLISM  4)9 

is  not  the  case  in  poisoning  due  to  the  "blood  poisons"  (for  lit. 
see  Loewi).  Apparently  such  asphyxial  glycosurias  are  essentially 
caused  by  a  stimulation  (by  the  asphyxial  blood)  of  the  "  piqure 
centre  "  in  the  medulla,  for  after  section  of  the  splanchnic  nerves  it 
does  not  occur. 

The  glycosuria  which  may  be  caused  by  caffeine  should  be  men- 
tioned in  this  place,  for  it,  too,  is  prevented  by  section  of  the 
splanchnic  nerves  and  is  evidently  due  to  direct  stimulation  of  this 
' '  diabetes  centre, ' '  which,  like  the  other  medullary-  centres,  is  directly 
stimulated  by  caffeine. 

It  would  appear  that  glycosuria  due  to  hyperglycaemia  may  also 
result  from  the  asphyxial  stimulation  of  a  peripheral  "  hypergly- 
caemia-producing  "  mechanism,  for  in  carbon  monoxide  poisoning 
glycosuria  occurs  even  after  section  of  the  splanchnics. 

SUPRARENAL  GLYCOSURIA. — Recent  investigations  have  furnished 
a  satisfactory  explanation  of  the  manner  in  which  the  stimulation  of 
the  diabetes  centre  produces  a  glycosuria.  The  subcutaneous  and, 
under  some  conditions,  the  intravenous  injection  of  epinephrin,  the 
active  principle  of  the  suprarenal  gland,  causes  a  glycosuria  of  con- 
siderable intensity.  Waterman  and  Smith  have  shown  that  the 
epinephrin  content  of  the  blood  is  increased  after  the  piqure  glyco- 
suricque,  while  A.  Meyer  has  demonstrated  that  after  extirpation 
of  the  suprarenals  the  piqure  does  not  cause  glycosuria.  It  has  also 
been  shown  that  after  extirpation  of  these  glands  or  section  of  their 
nerves  caffeine  no  longer  causes  an  increase  in  the  sugar  content  of 
the  blood.  It  would  therefore  appear  that,  like  the  piqure,  all  toxic 
stimulations  of  the  diabetes  centre  produce  glycosuria  in  the  last  in- 
stance by  an  action  on  the  adrenals. 

PHLORIDZIN  GLYCOSURIA. — A  glycosuria  of  entirely  different  type 
is  caused  by  the  internal,  subcutaneous,  or  intravenous  administration 
of  phloridzin.*  Its  effect  may  be  briefly  stated  to  be  the  lowering 
of  the  renal  threshold  value  for  the  excretion  of  sugar  from  the 
blood, — i.e.,  its  power  of  so  altering  conditions  in  the  blood  or  the 
kidney  that  the  kidney  excretes  sugar  when  the  blood  contains  less 
than  normal  amounts.  The  nature  of  this  change  is  not  at  all  clear, 
but  it  is  at  least  certain  that  it  is  a  local  change  taking  place  in  the 
kidney.  Possibly  it  consists  in  an  exaggeration  of  a  normally  prac- 
tically imperceptible  power  of  the  renal  parenchyma  to  form  or  split 
off  sugar  from  some  other  substances  or  some  sugar-containing  com- 
pound normally  present  in  the  blood. 

OTHER  TYPES  OF  RENAL  GLYCOSURIAS. — Glycosuria  may  also  result 
from  the  administration  of  many  poisons  which,  like  uranium,  the 
chromates,  corrosive  sublimate,  and  cantharidin,  produce  visible 
changes  in  the  renal  parenchyma.  As  in  these  glycosurias  it  has 
been  shown  that  hyperglycaemia  occurs  only  to  a  very  slight  degree 

*  A  glucoside  present  in  the  bark  of  the  roots  of  apple  and  cherry  trees. 


420  PHARMACOLOGY  OF  THE  METABOLISM 

and  by  no  means  regularly,*  it  may  be  concluded  that  they  are  due 
to  a  diminished  power  of  the  kidney  to  prevent  the  passage  of  sugar 
from  the  blood  into  the  urine. 

FORMATION  OF  GLYCURONIC  ACID. — A  quantitative  alteration  of  the 
carbohydrate  metabolism — namely,  the  increased  excretion  of  the 
esters  of  glycuronic  acid — results  from  the  administration  of  a  large 
number  of  different  organic  substances,  among  which  are  certain 
much-used  drugs,  such  as  chloral  hydrate,  phenol,  camphor,  many 
antipyretics,  morphine,  and  others  too  numerous  to  mention. 

Glycuronic  acid  is  chemically  very  closely  related  to  glucose,  its 
relation  being  that  of  an  acid  to  its  corresponding  alcohol,  as  shown 
by  the  accompanying  formulae: 

COH(CHOH)4COOH,  glycuronic  acid, 
COH(CHOH)4CH2OH,  glucose. 

In  the  body  it  occurs  only  in  organic  combination,  chiefly  with 
some  alcohol  or  with  phenol.  Under  normal  conditions  very  small 
quantities  of  it  are  formed,  and  are  combined  with  such  products 
of  intestinal  putrefaction  as  indol,  phenol,  etc.,  and  are  exeereted  in 
such  combinations  by  the  kidney.  After  administration  of  the  above- 
mentioned  substances,  which  in  the  body  are  reduced  or  oxidized  to 
phenols  or  alcohols,  the  glyeuronic  acid  is  formed  in  increased 
amounts,  or  is  not  further  combusted,  as  is  perhaps  normally  the  case, 
and  consequently  larger  amounts  are  excreted  in  the  urine  organically 
combined  with  these  substances.  Glycuronic  acid  is  probably  not 
derived  from  carbohydrates  already  formed  and  present  as  such  in 
the  body,  but,  like  glucose,  is  probably  formed  from  certain  mother 
substances  contained  in  the  proteid  molecule,  some  of  which  are 
changed  into  glucose  and  others  into  glycuronic  acid.  The  former  is 
transformed  into  and  stored  up  as  glycogen,  while  the  latter  is 
instantaneously  combusted  unless  it  is  protected  therefrom  by  ester- 
fication  (Fenyvessy}. 

These  combined  glycuronic  acids  reduce  alkaline  copper  solutions  (as  a 
rule,  only  if  previously  decomposed  by  boiling  with  acids)  and  are  laevorotatory, 
although  free  glycuronic  acid  is  dextrorotatory. 

BIBLIOGRAPHY 

Cavazzani  e  Soldaini:  Arch.  Ital.  de  Biol.,  1896,  vol.  25,  p.  465. 

Falta:  Volkmann's  Vortrage,   1905,  No.  405. 

Fenyvessy:  Arch,  intern,  de  Pharmacodyn.,  1903,  vol.  12,  p.  407. 

Kaufmann:  Ztschr.  f.  klin.  Med.,   1903,  vol.  48. 

Loewi:  v.  Noorden's  Handb.  d.  Path.  d.  Stoffw.,  1907,  vol.  2,  p.  711. 

Meyer,  A.:  Compt.  rend.  Soc.  Biol.,  1906,  p.  1123. 

Rudisch,  J.:  Arch.  f.  Verdauungskrankh.,  vol.   15,  p.  479. 

Waterman  and  Smith:  Pfliiger's  Arch.,   1908,  vol.    124. 

*HgCl2:  Graf,  Diss.  Wurzburg,  1895;  Richter,  Ztschr.  f.  klin.  Med.,  1900. 
Bd.  41.  Chromates:  Kossa,  Pfluger's  Arch.,  1902,  Bd.  88;  Blanck,  Med.  klin., 

1905.  Uranium:  Blanck,  loc.  cit. ;   Fleckseder,  Arch.  f.  exp.  Path,  und  Pharm., 

1906,  Bd.  56.     Cantharidin:  Richter,  Deut.  med.  Woch.,  1899,  No.  51;   Pollak, 
Arch.  f.  exp.  Path,  und  Pharm.,  1909,  Bd.  61,  and  1911,  Bd.  64. 


PURINE  METABOLISM  421 

ACIDOSIS. — Many  variations  and  disturbances  may  occur  in  the 
chemical  decomposition  of  the  tissues  and  food-stuffs,  by  which  ordi- 
narily the  end  products  of  metabolism  are  formed.  While  these 
variations  from  the  normal  at  times  produce  hardly  appreciable  effects 
in  the  total  energy  balance,  they  may  have  results  which  are  of  great 
importance  for  the  welfare  of  the  organism.  Thus,  the  formation  and 
excretion  of  abnormal  amounts  of  acids,  which  occur  in  poisoning  by 
various  agents,  result  only  in  a  slight  loss  of  energy,  but,  under  some 
conditions,  may  so  alter  the  chemical  conditions  throughout  the  whole 
body  as  to  produce  most  serious  results. 

PURINE  METABOLISM 

The  metabolism  of  the  purines,  pathological  disturbances  of  which 
express  themselves  as  gout,  is  of  especial  practical  importance.  Little 
is  known  of  their  causation,  and  consequently  any  successful  treat- 
ment of  these  causes,  in  so  far  as  this  is  actually  possible,  rests  on  no 
rational  foundation.  The  first  assumption  naturally  made,  that  the 
excretion  of  the  uric  acid  retained  in  the  tissues  and  in  the  blood 
could  be  hastened  and  increased  by  the  administration  of  alkalies 
and  other  uric-acid  solvents  (piperazine,  lysidine,  etc.) ,  has  been  found 
to  be  erroneous.  While  the  salicylates  increase  the  excretion  of  uric 
acid,  they  do  not  exert  any  material  influence  on  the  course  of  the 
disease  (for  lit.  see  Ulrici  and  v.  Noorden). 

ATOPHAN. — The  investigations  of  Nicolaier  and  Dohrn  have  shown 
that  the  excretion  of  uric  acid  is  markedly  increased  by  the  admin- 
istration of  the  different  quinoline-carbonic  acids  and  their  derivatives. 
2-Phenylquinoline-4  carbonic  acid,  to  which  the  trade  name  of 
atophan  has  been  given,  possesses  this  power  to  an  especially  high 
degree.  According  to  Weintraud  and  other  clinical  observers,  very 
favorable  results  may  be  obtained  in  cases  of  gout  by  the  admin- 
istration for  long  periods  of  0.5-1.0  gm.  of  this  drug  three  or 
four  times  daily.  Large  quantities  of  alkaline  waters  should  be 
drunk  during  this  treatment,  in  order  to  prevent  the  deposition  of 
uratic  concretions  in  the  kidney  or  bladder. 

No  drugs  are  known  which  have  any  power  of  influencing  those 
anomalies  of  metabolism  known  as  oxaluria  and  phosphaturia. 

BIBLIOGRAPHY 

Nicolaier  u.  Dohrn:  Deut.  Arch.  f.  klin.  Med.,   1908,  vol.  93,  p.  331. 
v.  Noorden:   Handb.  d.  Path.  d.  Stoffw.,  1906,  p.  131. 
Ulrici:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46,  p.  321. 
Weintraud:  Ther.  d.  Gegenw.,  1911,  p.  97. 


CHAPTER  XIII 

PHARMACOLOGY  OF  THE  MUSCLES 

PHYSIOLOGY  AND  ANATOMY 

THERE  are  three  types  of  muscle-cells  present  in  the  body, — the 
striated  or  voluntary,  the  smooth  or  involuntary  muscles,  and  the 
cardiac  muscles,  all  differing  from  one  another  in  their  chemical 
composition,  their  histological  structure,  and  their  physiological 
functions. 

The  effects  of  pharmacological  agents  on  the  smooth  and  the 
cardiac  muscles,  the  vegetative  muscle,  has  been  discussed  in  the 
chapters  dealing  with  the  pharmacology  of  the  circulation  and  of  the 
vegetative  nervous  system.  Here  a  direct  action  on  the  muscles  them- 
selves  could  only  very  seldom  be  assumed  with  certainty,  for,  as  a  rule, 
the  actions  discussed  affected  the  terminal  nervous  organs  (nerve- 
endings)  or  the  myoneural  intermediary  substance  which  does  not 
actually  belong  to  the  integral  substance  of  the  muscle-cells,  even 
though  it  does  not  degenerate  after  section  of  the  nerves.  In  the 
case  of  certain  pharmacological  actions  this  was  apparent  from  the 
peculiar  effects  of  the  drugs,  which  were  explained  by  the  character 
of  the  innervation,  so  that  they  expressed  themselves,  as  in  the  case 
of  epinephrin,  sometimes  as  stimulation  and  sometimes  as  inhibition, 
while  similar  phenomena  were  also  observed  in  connection  with  the 
actions  of  the  group  of  "  autonomic  poisons."  The  only  pharma- 
cological substances  which  probably  stimulate  all  the  smooth  muscle 
cells  in  the  body  are  the  substances  of  the  digitalis  group  and  the 
salts  of  barium. 

The  functional  capacity  of  the  striated  muscles  is,  like  that  of  the 
smooth  muscles,  dependent  in  general  not  only  on  the  structure  and 
chemical  composition  of  their  organic  constituents, — proteids,  lipoids, 
and  carbohydrates, — but  also  on  their  inorganic  constituents, 
especially  the  cations  (Hober).  Thus,  Overton  has  shown  that  the 
excitability  of  muscles  is  entirely  abolished  when  Na  ions  are  with- 
drawn from  them  or  from  the  fluid  between  their  cells  by  sequi- 
molecular  sodium-free  solutions,  such  as  cane-sugar  solutions,  while 
Loeb  has  shown  that  it  is  tremendously  increased  by  removal  of  the 
calcium  ions.  This  latter  is  of  toxicological  interest  in  so  far  as  the 
fibrillary  muscle  twitchings  in  poisoning  by  agents  which  precipitate 
calcium  (oxalic  and  citric  acids)  may  be  attributed  to  the  removal 
of  calcium. 

It  is  also  certain  that  the  water  content  of  muscles  distinctly  in- 
fluences their  functional  capacity  (Demoor  et  Philippson),  extreme 
dehydration  having  a  marked  effect,  as  will  be  shown.  Probably 
422 


PHYSIOLOGY  AND  ANATOMY  423 


an  abnormally  large  water  content  will  also  have  a  harmful  effect. 
One  of  the  ways  in  which  this  may  be  induced  is  by  appropriate  feed- 
ing, Tsuboi  having  found  in  rabbits,  fed  chiefly  on  potatoes,  the  water 
content  of  the  muscles  2-7  per  cent,  higher  and  their  haemoglobin  con- 
tent 2-4  per  cent,  lower  than  that  of  normal  controls. 

The  water  content  of  muscle  is  diminished  by  work,  the  relative 
increase  of  the  dry  material  being  the  most  important  factor  in  the 
hypertrophy  resulting  from  work,  except  in  the  case  of  the  cardiac 
muscles,  which  alone  when  hypertrophied  show  only  a  general  in- 
crease in  weight  without  any  alteration  in  the  proportion  of  their 
constituents  ( Gerhartz ) . 

The  voluntary  muscles  are  the  organs  for  motion  and  for  produc- 
tion of  heat.  Their  fibres  are  composed  of  the  apparently  homo- 
geneous sarcoplasma  and,  imbedded  therein,  the  anisotropic  trans- 
versely striated  fibrils.  According  to  the  relative  amounts  of  these 
two  elements  (Grutzner)  or  their  reciprocal  arrangement  (Paukul), 
two  types  of  muscle-fibres  may  be  differentiated, — those  richer  in 
plasma,  the  so-called  red  muscles,  which  can  remain  contracted  for 
long  periods,  and  those  containing  less  plasma,  the  so-called  white 
muscles,  which  contract  and  relax  quickly  (Ranvier,  Erb).  The 
quickly  acting  elements  are  the  anisotropic  fibrils  and  the  slowly 
acting  the  sarcoplasma  (Botazzi,  Joteyko). 

These  two  elements  appear  to  have  entirely  different  chemico- 
physical  properties  and  equally  different  physiological  and  pharma- 
cological reactions.  "While  the  rapid  twitchings  of  the  fibrils  are  ac- 
companied by  an  active  production  of  heat  and  marked  chemical 
changes,  and  accordingly  relatively  soon  result  in  exhaustion, — that 
is,  in  the  consumption  of  the  readily  available  substances  and  the  pro- 
duction of  ''fatigue  substances," — the  slowly  starting  and  persis- 
tent shortening  of  the  sarcoplasma,  which  at  times  may  last  for  hours 
or  even  weeks  (as  in  contractures),  appears  to  cause  no  measurable 
production  of  heat  (Brissaud) .  It  would  appear,  therefore,  that  this 
latter  type  of  contraction  represents  only  another  physical  state  and 
normally  exhibits  none  of  the  ordinary  phenomena  of  fatigue.  This 
is  especially  remarkable  in  persistent  hysterical  contractures. 

Both  these  types  of  muscular  contractions  are  under  the  control 
of  the  nervous  system,  and  are  without  doubt  governed  by  separate 
and  distinct  mechanisms,  or  at  least  by  different  stimuli,  which  in 
the  case  of  voluntary  movements  are  excited  in  the  central  nervous 
system  and  which  may  cause  either  short  contractions  or  a  more  or 
less  persistent  contraction,  depending  on  the  character  of  the  stimulus. 
The  effective  artificial  stimuli  are  also  different,  the  quick  shocks  of 
the  induced  current  exciting  the  anisotropic  fibrils,  and  the  constant 
current  the  sarcoplasma. 

Chemical  stimulation  of  a  nerve — as,  for  example,  by  concentrated 
salt  solution  applied  to  the  nerve  of  a  frog's  muscle-nerve  prepara- 


424  PHARMACOLOGY  OF  THE  MUSCLES 

tions — excites  chiefly  the  persistent  contraction  of  the  sarcoplasma,  to 
which  may  be  superadded  twitchings  of  the  fibrillary  substance,  these 
being  especially  well  develdped  if  such  twitchings  are  periodically 

induced  by  the  induced  current  (Fig.  47) 
(Limb  our g). 

DIRECT  AND  INDIRECT  PHARMACOLOGICAL 
ACTIONS. — From  the  above,  it  is  clear  that 
the  functional  activity  of  the  muscles  may 
be  influenced  by  pharmacological  agents 
acting  either  directly  on  the  muscles  or 

by  Kci.  4fe?fiSKSl  through  the  nervous  system.  As  is  well 
electric  stimulation  every  10  sec-  known,  the  ability  of  a  muscle  to  contract 

depends  almost  entirely  on  the  nervous  im- 
pulses which  are  constantly  reaching  it,  even  when  they  cause  no  per- 
ceptible contractions.  This  is  most  strikingly  shown  by  the  much 
more  rapid  occurrence  of  rigor  (either  rigor  mortis  or  that  of  toxic 
origin)  in  muscles  with  intact  nerves  than  in  those  deprived  of  their 
nerves,  or,  what  is  essentially  the  same  thing,  in  curarized  muscles 
(Kerry"). 

It  is,  therefore,  conceivable  that,  in  conditions  of  purely  muscular 
weakness  or  lessened  functional  power  of  the  muscles,  the  strengthen- 
ing of  the  reflex  motor  influences,  or  their  facilitation  by  such  drugs 
as  strychnine  or  by  electric  stimulation  of  the  motor  nerves,  may 
not  only  subjectively  facilitate  muscular  action,  but,  by  continuously 
keeping  the  nerve  paths  open  (Bahnung),  may  also  maintain  and 
stimulate  the  chemical  processes  on  which  muscular  contraction  and 
activity  depend  (Robertson). 

CONTRACTURE. — If  a  muscle  becomes  fatigued  by  continuous  exer- 
tion or  by  maximal  tetanic  contraction,  the  excitability  of  the  sarco- 
plasma— or,  more  correctly  expressed,  its  tendency  to  shorten — is  in- 
creased, the  muscle  passing  into  the  well-known  permanent  shortening, 
Tiegel's  contracture.  In  frogs,  which  at  the  end  of  the  winter  are  in  a 
state  of  malnutrition,  this  condition  develops  very  readily,  so  that  their 
muscles  often,  after  a  single  powerful  stimulation,  contract  and  re- 
main contracted  for  a  considerable  period.  In  myotonia  congenita, 
or  Thompson's  disease,  the  muscles  behave  similarly,  the  muscle  tone 
being  absent  during  persistence  of  these  contractures,  as  is  also  the 
case  with  hysterical  contractures  (Herz).  In  this  condition  also 
the  sarcoplasma  is  not  normal,  exhibiting  under  the  miscroscope  an 
abnormal  structure  (Schieferdecker) .  An  analogous  disturbance  is 
found  in  many  other  diseases  of  the  muscles — e.g.,  in  pseudohyper- 
trophic  muscular  paralysis  (Mendelsohn)  and  in  athetosis  (Kaiser). 
This  pathological  condition  may  be  induced  by  dehydration — by  con- 
centrated salt  solutions  or  glycerin  (Santesson,  Gregor),  as  also 
by  numerous  poisons,  but  in  an  especially  striking  way  by  veratrine. 


VERATRINE  425 

BIBLIOGRAPHY 

Bottazzi:  Dubois'  Arch.,   1901,   p.   377. 

Brissaud  et  Regnard:  Bull.  Soc.  Biol.,  1881,  vols.  13-14,  p.  348. 

Demoor  et  Philippson:   Bull,  de  1'Acad.  d.  MM.  de  Belg.,  1908-09,  p.  655. 

Erb:   Die  Thomsensche  Krankheit,  Leipzig,  1886. 

Gerhartz:  Pfliiger's  Arch.,  1910,  vol.  133,  p.  397. 

Gregor:  Pfluger's  Arch.,  1904,  vol.  101. 

Griitzner:  Bresl.  arztl.  Zeit.,  1883-1886. 

Herz:  Wien.  klin.  Woch.,  1900,  p.  1178. 

Hober:  Pfliiger's  Arch.,  1904,  vols.  101-102. 

Hober:  Pfliiger's  Arch.,  1905,  vol.  106. 

Joteyko:  Etude  sur  la  contrac.  tonique,  etc.,  Inst.  Solvay  Trav.,   1902,  vol.  5f 

p.  229. 

Kaiser:  Neur.  Zbl.,  1897,  No.  15,  vol.  16,  p.  674. 
Kerry  u.  Rost:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  39. 
Limbourg:  Pfliiger's  Arch.,  1887,  vol.  41. 
Loeb:  Fick's  Festschrift,  1889. 

Mendelsohn:  Compt.  rend.  Acad.  des  sciences,  1883. 
Overton:   Pfluger's  Arch.,   1902,  vol.  92. 
Paukul:   Dubois'  Arch.,   1904,  p.   100. 
Ranvier:  Compt.  rend.,  1873,  vol.  77,  p.  1030. 
Robertson:   Biochem.   Ztschr.,    1908,   p.   287. 
Santesson:   Skand.  Arch,  phys.,  1903,  vol.  14,  p.  1. 

Schieferdecker  u.  Schultze :  Deut.  Ztschr.  f .  Nervenheilk.,  1903,  vol.  25. 
Teuboi:  Ztschr.  f.  Biol.,  1903,  vol.  44. 

VERATRINE 

Veratrine  (Bohm),  obtained  from  the  seeds  of  Veratrum  sabadilla 
and  V.  viride,  is  a  mixture  of  alkaloids  of  which  cevadine  (Freund) 
is  the  most  important. 

Locally  it  is  very  irritant  to  the  sensory  nerves,  very  small  amounts  being 
sufficient  to  cause  sneezing,  burning  of  the  eyes,  etc.  When  rubbed  into  the 
akin,  it  first  causes  a  painful  pricking  and  burning  sensation  and  later 
anaesthesia.  Veratrine  ointment  has,  therefore,  been  successfully  employed  in 
trigeminal  neuralgia  and  sciatica. 

In  connection  with  this  action  on  the  sensory  nerve-endings  it  may  be  that 
this  drug's  action  is  not  limited  to  these  structures  alone,  for  it  must  be 
admitted  that  it  may  possibly  pass  into  and  along  the  nerves  and  reach  central 
portions  of  them,  for  Joteyko  has  made  the  remarkable  observation  that 
veratrine  in  the  frog,  unlike  almost  all  other  substances,  can  spread  along 
in  the  nerves  and  relatively  quickly  transverse  long  stretches,  even  after 
complete  stoppage  of  the  circulation.  This  would  explain  the  fact  that,  even 
after  local  application  of  this  drug,  parsesthesias  occur  at  remote  points 
(Kunkel) ,  as  well  as  the  fact  that,  in  animals  poisoned  by  its  subcutaneous 
administration,  the  characteristic  alteration  of  the  phenomena  accompanying 
stimulation,  which  may  be  observed  in  the  muscle  after  veratrine,  may  be  also 
demonstrated  in  the  electromotor  phenomena  occurring  in  the  nerves  (Garten). 

Veratrine  acts  energetically  on  the  central  nervous  system,  causing  vomit- 
ing, dyspnoea,  and  convulsions,  and  finally  paralysis  of  the  medullary  centres. 

ACTION  ON  VOLUNTARY  MUSCLES. — The  most  thoroughly  investi- 
gated action  of  veratrine  is  that  on  striated  muscle,  which  in  warm- 
blooded animals  manifests  itself  by  peculiar  spastic  and  difficult  move- 
ments, while  in  the  frog  this  action  is  even  more  clearly  developed. 

If  a  frog  be  poisoned  with  a  small  amount  (1/20  mg.)  of  veratrine, 
after  a  short  time  a  characteristic  alteration  of  its  movements  is  noted, 
the  frog  springing  quite  normally,  but  then  lying  for  a  time  stretched 


PHARMACOLOGY  OF  THE  MUSCLES 


out  and  only  gradually  becoming  able  to  bend  his  legs  again  and  to 
pull  them  up.  The  same  muscular  phenomena  may  be  observed  in 
nerve-muscle  preparations,  even  after  curarization ;  contractions  in- 
duced by  the  induced  current  occur  immediately,  but  either  the 
muscle  remains  contracted  or  the  contracted  muscle  after  starting 
to  relax  promptly  contracts  again  before  it  has  completely  relaxed 
and  this  time  remains  contracted  for  a  considerable  period 
(Mostinzki}.  If  the  stimuli  follow  each  other  rapidly,  the  contracture 
disappears,  for  the  overexcitable  sarcoplasma  exhausts  itself  and 
breaks  down,  becoming  under  these  conditions  fatigued  more  quickly 
than  the  fibrillar  substance,  which  ordinarily  tires  more  readily  (see 
Fig.  48). 

The  increased  extent  of  the  contractions  and  the  augmented  pro- 
duction of  heat  indicate  that  not  only  the  sarcoplasma  but  also  the 


FIG.  48. — a,  normal  muscular  contraction;  b,  c,  veratrinc  contractions;  d,  influence  of 
fatigue  on  veratrinized  muscle. 

fibrillar  substance  is  rendered  more  excitable  by  veratrine,  the  total 
functional  capacity  of  the  muscle  being  increased,  as  was  demon- 
strated by  Dreser,  using  the  frog's  gastrocnemius. 

Other  Actions  of  Veratrine. — Veratrine  exerts  a  similar  action  on  the  cardiac 
muscle,  the  contraction  being  prolonged,  or,  better  expressed,  passing  off  more 
slowly.  By  this  action  on  the  cardiac  muscle  the  pulse  may  be  markedly 
slowed,  and,  as  a  result  of  a  depression  of  the  centres  for  the  regulation  of  the 
temperature,  the  temperature  may  fall  after  the  administration  of  this  drug, 
which  formerly  was  extensively  employed  as  an  antipyretic.  The  action  on 
the  heart  and  the  muscles  might  well  be  therapeutically  useful  were  it  not  for 
the  fact  that  these  effects  may  usually  be  secured  only  by  doses  which  produce 
a  profound  poisoning  of  the  central  nervous  system  and  cause  violent  and 
dangerous  disturbances  of  the  circulation  and  respiration.  It  was  formerly 
used  in  the  dangerously  large  amounts  of  0.05  gm.  for  single  doses  and  0.2  gm. 
per  diem. 

Yeratrum  viride  and  V.  album  contain  protoveratrine,  an  alkaloid 
related  to  veratrine  but  much  more  dangerous  (Eden,  Salzberger). 


STRYCHNINE  427 

Its  actions  differ  considerably  from  those  of  veratrine,  but  no  benefit 
is  to  be  expected  from  its  therapeutic  employment. 

[There  is  good  ground  for  believing  that  veratrine  slows  the 
pulse  in  man  as  a  result  of  central  vagus  stimulation  rather  than  as 
a  result  of  its  typical  action  on  the  cardiac  muscle.  This  drug  is 
also  used  by  competent  authorities  in  the  treatment  of  uraemia  and 
of  eclampsia,  particularly  when  the  blood-pressure  is  high.  Under 
these  conditions  it  often  markedly  lowers  the  blood-pressure.  How- 
ever, the  weight  of  opinion  appears  to  be  against  its  employment  for 
these  indications. — TR.] 

BIBLIOGRAPHY 

Bohm:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  58. 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27. 

Eden:  Arch.   f.   exp.   Path.   u.   Pharm.,    1892,   vol.   29. 

Fick  u.  Bohm.:   Wiirzb.  Arb.,  1872. 

Freund  u.  Schwarz:   Ber.  der  Deut.  Chem.  Ges.,  1899,  vol.  32,  p.  800. 

Garten:   Pfluger's  Arch.,  1899,  vol.  77. 

Jotekyo:   Inst.  Sol.  Trav.,  etc.,  1902,  vol.  5,  p.  271. 

Kunkel's  Handbuch,  1901,  p.  765. 

Mostinski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1904,  vol.  51. 

Salzberger:  Arch.  d.  Ph.,  1890. 

STRYCHNINE. — Paderi  states  that  the  tone  of  a  frog's  gastroc- 
nemius,  isolated  from  the  central  nervous  system,  is  augmented  by 
very  small  doses  of  strychnine,  the  extent  and  duration  of  its  con- 
tractions being  increased,  and  that  the  same  is  true  for  the  muscles 
of  the  frog's  stomach.  These  observations  appear  to  him  to  support 
the  clinical  employment  of  very  small  doses  of  this  drug  as  a  so- 
called  "  tonic." 

BIBLIOGRAPHY 

Paderi:  Arch.  Ital.  Biol.,  1893,  vol.  19,  and  La  Terap.  Med.,  1892. 

Of  much  greater  practical  importance  than  the  above-described 
qualitative  alteration  of  muscular  action,  produced  by  veratrine,  is 
the  causation  by  drugs  of  a  quantitative  alteration  of  the  functional 
capacity  of  the  muscles,  as  measured  by  the  extent  to  which  they  can 
contract  and  by  their  absolute  power, — i.e.,  the  largest  weight  they 
can  lift. 

MUSCULAR  DEPRESSANTS 

A  diminution  of  their  functional  capacity,  even  to  complete  paral- 
ysis, is,  as  is  well  known,  a  symptom  of  many  neuromuscular  patho- 
logical conditions,  and  is  usually  associated  with  atrophy  or  degenera- 
tion of  the  muscles.  Experimentally,  also,  such  paralysis  of  the 
muscle-fibres  may  be  produced,  particularly  in  cold-blooded  animals, 
by  the  administration  of  apomorphine  or  salts  of  Cur  Pb,  or  As 
(Harnack}. 

In  chronic  lead  poisoning  in  man,  a  paralysis  often  occurs,  especially  in 
the  extensors  of  the  arm.  Whether  this  be  due  primarily  to  changes  in  the 
muscle-cells  or  in  their  nerves  or  to  degeneration  in  the  cord  is  still  uncertain. 


428  PHARMACOLOGY  OF  THE  MUSCLES 

The  predisposition  of  the  extensors  of  the  arm  to  this  affection  is  probably 
due  to  the  greater  use  of  these  muscles,  for  in  small  children  and  in  animals 
the  paralysis  caused  by  lead  is  atypical  in  its  distribution,  the  lower  ex- 
tremities being  affected  as  frequently  as  are  the  upper  (Stieglitz,  Neumann, 
Edinger,  Teleky). 

BIBLIOGRAPHY 

Edinger:  Deutsche  med.  Woch.,  1904,  No.  45,  p.  1633;  1904,  No.  49,  p.  1800; 

1904,  No.  52,  p.  1921. 

Harnack:  Arch.  f.  exp.  Path.  u.  Pharm.,  1874,  vol.  3,  and  1878,  vol.  9. 
Neumann,  W.:  Diss.,  Bern,  1883. 
Stieglitz:  Arch.  f.  Psychiatric,  1892,  vol.  24,  p.  50. 
Teleky,  E.:  Zur  Kasuistik  d.  Bleilahmung,  D.  Z.  f.  Nervenheilk.,  1909,  vol.  37, 

p.  234. 

MUSCULAR  STIMULANTS 

Caffeine  and  theobromine  and,  although  in  a  different  manner, 
alcohol  may  increase  the  working  power  of  muscle. 

CAFFEINE 

In  frogs — especially  readily  in  R.  temporaria  (Schmiedeberg)— 
large  doses  of  caffeine  cause  a  maximal  shortening  and  rigor  of  the 
muscles,  which  may  be  observed  equally  well  in  the  muscles  of  the 
intact  frog  or  under  the  microscope  in  teased  muscle  preparations 
at  the  moment  of  contact  with  a  solution  of  caffeine.  Eigor  may  also 
be  induced  in  warm-blooded  animals  by  injecting  caffeine  into  an 
artery  (Lakur). 

"With  less  pronounced  caffeine  action  there  is  an  increase  in  the 
muscle's  irritability  and  ability  to  contract  when  stimulated,  so  that 
it  not  only  responds  to  a  slighter  stimulus  (Paschkis),  but  exhibits  a 
greater  capacity  for  work  and  an  increase  in  absolute  power  (Dreser) . 
Xanthine  and  creatin  produce  similar  effects.  In  man  also  this  drug 
increases  the  capacity  for  muscular  work,  as  has  been  shown  chiefly 
by  exact  ergographic  investigations. 

Muscular  Fatigue. — Various  parts  of  the  neuromuscular  appara- 
tus are  involved  in  the  phenomena  of  fatigue,  the  intramuscular 
nerve-endings  and  the  muscle-cells  being  primarily  affected,  and 
secondarily  the  psychomotor  functions  of  the  central  nervous  system 
(Joteyko).  Both  psychophysical  investigations  (Krdpelin)  and  the 
mathematical  analysis  of  ergographic  fatigue  curves  (Henri)  indicate 
that  the  height  of  the  lift  is  chiefly  dependent  on  the  condition  of  the 
peripheral  neuromuscular  organ,  while  the  number  of  contractions 
which  take  place  before  complete  exhaustion  occurs  depends  on  the 
condition  of  the  motor  centres.  That  is  to  say,  in  myogenic  fatigue 
the  height  of  the  lift  immediately  or  very  quickly  diminishes  some- 
what and  then  falls  very  gradually,  while  in  central  fatigue  the 
height  of  the  lift  is  at  first  normal  but  very  rapidly  falls  to  zero, 
so  that  the  number  of  liftings  accomplished  is  much  less  than  is  nor- 
mally the  case  (Fig.  49). 


CAFFEINE  AND  ALCOHOL 


429 


Effect  of  Caffeine  in  Fatigue. — In  fatigue,  when  the  capacity  for 
muscular  work  is  already  diminished,  caffeine  increases  the  total  per- 
formance of  muscular  work.  This  is  due  chiefly  to  a  direct  beneficial 
action  on  the  muscle-cells  (Mosso),  and  to  some  extent  to  its  favorable 
action  on  the  central  motor  functions  (Krapelin,  Koch'). 


FIG.  49. — Ergographic  curves. 

These  observations  furnish  a  confirmation  of  the  experience  of 
mountain-climbers  and  soldiers,  who  long  ago  discovered  the  power 
of  coffee,  tea,  etc.,  to  overcome  fatigue  during  exhausting  exertion 
or  marches.  Creatin,  which  is  a  constituent  of  meat  broths,  influences 
the  muscle  function  similarly  to,  though  less  powerfully  than,  caffeine. 


BIBLIOGRAPHY 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  50. 
Henri  u.  Joteyko:  Compt.  rend.  Acad.  des  sciences,  Paris,  1903. 
Joteyko:  Art.  "Fatigue,"  in  Richet,  Diet.  d.  phys.,  here  compl.  lit. 
Koch:  Ergographische  Studien,  Diss.,  Marbourg,   1894. 
Krapelin  u.  Hoch:  Psycholog.  Arbeiten,  1895. 
Lakur:  Virchow's  Arch.,  1895,  vol.  141,  p.  479. 
Mosso,  U.:  Arch.  ital.  biol.,  1893,  vol.   19. 
Paschkis  u.  Pal:   Wien.  med.  Jahrb.,  1886,  p.  611. 
SchmieJeberg:  Arch.  f.  exp.  Path.  u.  Pharm.,   1873,  vol.  2. 

ALCOHOL 

THE  ACTION  OF  ALCOHOL  ON  MUSCLE  FUNCTION  is  much  more  com- 
plicated. That  in  man  small  amounts  of  alcohol  (0.3-0.5  gm.  per 
kilo,  body  weight)  may  under  some  conditions  facilitate  intense 
muscular  activity  and  increase  the  power  of  performance  is  well 
known,  but  it  is  equally  well  known  that  they  may  produce  a  directly 
opposite  effect.  These  effects  result  from  the  action  of  alcohol  on  the 
central  nervous  system  and  on  the  muscles  and  the  nerve-endings. 

Action  through  the  Central  Nervous  System. — In  a  previous  sec- 
tion (Pharmacology  of  the  Central  Nervous  System)  it  has  been  shown 
that  one  of  the  early  actions  of  alcohol  is,  on  the  one  hand,  to  facilitate 


430 


PHARMACOLOGY  OF  THE  MUSCLES 


the  excitation  of  motor  impulses  and,  on  the  other,  to  blunt  the  percep- 
tion of  sensory  stimuli.  Muscular  activity  may  be  favorably  in- 
fluenced both  by  the  facilitation  of  the  central  psychomotor  processes 
and  by  the  more  or  less  complete  suppression  of  the  fatigue  reflexes 
resulting  from  muscular  exertion  (Frey}. 

Direct  Action  on  Muscle. — Alcohol  exerts  two  actions  on  the 
muscle  itself  which  are  antagonistic  to  each  other.  The  capacity 
of  the  muscles  for  work  and  perhaps  also  their  readiness  to  contract 
are,  in  warm-blooded  animals,  somewhat  unfavorably  influenced 
from  the  start,  as  shown  by  W.  Lombard  and  by  Frey  for  the  flexors 
of  the  forearm  in  man. 

Scheffer  found  that  at  first  alcohol  caused  an  increase  of  the  excitability 
of  the  frog's  nerve-muscle  preparation,  which  did  not  occur  with  curarized 
preparations.  Verzas,  using  somewhat  longer  dosage,  obtained  the  same  in- 
crease of  excitability,  even  after  curare,  and  an  augmentation  of  functional 
power.  These  effects  were  produced  both  by  methyl  alcohol  ( 1/80  of  the  body 
weight)  and  by  ethyl  alcohol  (1/500-1/200  body  weight).  Larger  doses  had  a 
harmful  effect,  which  was  less  marked  with  methyl  than  with  ethyl  alcohol. 


Normal  curve. 


Alcohol  curve. 
FIG.  50. — Interval  four  seconds. 


In  spite  of  this,  however,  alcohol  may  increase  the  total  perform- 
ance of  a  muscle  not  by  increasing  the  power  or  extent  of  the  in- 
dividual contractions,  but  by  increasing  the  endurance  of  the  muscle, — 
i.e.,  increasing  its  ability  to  recuperate  after  each  contraction.  As  a, 
result  of  this  action,  exhaustion  from  continuous  and  therefore  rapidly 
exhausting  work  is  distinctly  postponed.  Joteyko  's  ergographic  curves. 
(Fig.  50)  illustrate  this  well.  In  isometric  tasks  also  the  total  per- 
formance is  increased  (Hellsten). 

The  increased  recuperative  capacity  of  muscles  treated  with  alco- 
hol is  hardly  susceptible  of  explanation  except  on  the  premise  that 
alcohol  furnishes  food  and  energy  to  the  muscles.  This  has  been 
assumed  by  Frey,  Schnyder,  and  Joteyko,  and  is  confirmed  by  the 
mathematical  analysis  of  Durig's  experiments,  in  which  he  determined 
the  effects  of  alcohol  on  the  respiratory  coefficient  and  the  production 
of  energy.  If  alcohol,  which  is  readily  oxidized  to  C02  and  H,0,  is 
oxidized  in  place  of  other  constituents  of  muscle,  it  is  clear  that  there 
will  be  found  smaller  amounts  of  those  decomposition  products  of  the 
cellular  material  whose  accumulation  plays  an  important  role  in  the 
causation  of  fatigue.  The  analysis  of  Joteyk&'s  alcohol  muscle  curves 
speaks  strongly  for  this  view. 


ALCOHOL  AS  FOOD  431 

Joteyko  sets  up  the  following  equation,  n  =  H  +  btz —  at3  —  ct,  as  one  con- 
stantly true  for  ergographic  curves,  in  which  n  =  the  ordinate,  the  height  of  the 
lift;  £  =  the  abscissa,  the  interval  of  time;  H  =  ihe  height  of  the  lift  at  the 
start,  and  a,  b,  and  c  are  variables,  a  representing  the  formation  of  "  fatigue 
substances,"  6  the  central  motor  facilitation,  and  o  the  consumption  of  the 
muscle's  store  of  carbohydrates  and  reserve  materials.  With  the  use  of  this 
formula  it  may  be  shown  that  in  the  curves  obtained  under  the  influence  of 
alcohol  the  value  of  a  (i.e.,  the  formation  of  fatigue  substances)  is  smaller  than 
in  normal  curves. 

A.  Fick  opposes  the  assumption  that  alcohol  is  combusted  and  supplies, 
muscular  energy,  by  objections  based  on  mathematical  calculations  which 
indicate  that  in  fatigue,  as  it  occurs  in  ergographic  experiments,  no  marked 
lessening  of  the  supply  of  carbohydrate  fuel  can  occur,  and,  therefore,  there 
is  no  ground  for  concluding  that  muscular  recuperation  under  the  influences  of 
alcohol  is  due  to  supplying  the  lacking  fuel.  The  correctness  of  this  criticism 
cannot  be  experimentally  tested,  for  we  do  not  know  whether  all  the  energy- 
Bupplying  material  in  the  muscles  (carbohydrates)  is  equally  readily  available. 
Probably  this  is  not  the  case,  for  it  is  possible  to  cause  a  complete  disappearance 
of  muscle  glycogen  only  by  extreme  forced  muscular  contractions.  This  as- 
sumption is  also  rendered  improbable  by  the  marked  diminution  of  the  sugar 
in  the  blood  which  occurs  during  moderate  muscular  exertion  at  a  time  when 
the  muscle  certainly  contains  considerable  glycogen  (Weiland).  Fick's  critique 
could  be  equally  well  used  to  disprove  the  recuperative  effects  of  small  amounts 
of  sugar  (30  gm.)  in  extreme  exhaustion.  This  latter  has  been  certainly 
proved  (Schumberg,  Joteyko),  and  can  hardly  be  explained  otherwise  than  as. 
the  result  of  supplying  energy. 

ALCOHOL  A  FOOD  IN  CASE  OF  NEED. — From  the  above  discussion  it 
is  justifiable  to  conclude  that  alcohol  will  cause  no  objective  increase 
of  the  working  power  of  strong  and  unexhausted  muscle  although 
bringing  about  a  subjective  facilitation,  while  in  conditions  of  exhaus- 
tion it  will  positively  increase  the  failing  muscular  power.  It  may, 
therefore,  be  useful  as  a  promptly  though  temporarily  acting  means 
of  recuperation  and  strengthening  in  case  of  marked  exhaustion  from 
work  which  must  not  be  interrupted.  Under  such  conditions  it  is 
for  the  time  being  more  effective  than  sugar  or  other  food,  for,  on 
account  of  its  solubility  in  lipoids,  it  is  very  rapidly  absorbed  and 
taken  up  by  all  the  cells. 

Not  a  Complete  Food. — Alcohol  is,  however,  not  a  complete  or 
even  an  approximately  satisfactory  substitute  for  food  for  muscle, 
for  with  larger  doses,  such  as  are  necessary  for  the  accomplishment 
of  any  considerable  amount  of  work,  its  toxic  action  on  the  central 
nervous  system  becomes  manifest  and  interferes  with  the  power  to 
work.  Moreover,  even  with  moderate  not  markedly  toxic  doses  both 
Chauveau  and  Durig  have  shown  that  the  utilization  of  the  energy 

energy  produced    ,    .  ,  .  , 

produced  is  not  good:     J... — —- being  much  less  than  when 

energy  utilized 

food  containing  no  alcohol  is  taken.  "With  this  fuel  (alcohol)  not 
only  does  the  machine  work  more  slowly  than  when  the  usual  fuel 
(ordinary  food)  is  used,  but,  when  the  attempt  is  made  to  use  alcohol 
as  fuel,  the  machine  itself  is  for  the  time  being  damaged  and,  utiliz- 
ing the  available  fuel  uneconomically,  performs  less  work  than  it 
should."  It  is  not  necessary  to  state  that  under  certain  conditions 


432  PHARMACOLOGY  OF  THE  MUSCLES 

the  heat  resulting  from  the  combustion  of  alcohol  may  be  of  ad- 
vantage to  the  body  by  sparing  other  fuel  material. 

THE  ROLE  OF  ALCOHOL  AS  A  FOOD. — Not  only  does  the  oxidation 
of  alcohol  supply  heat  to  the  body,  but  it  also  supplies  energy  which 
may  be  directly  utilized  by  various  organs  in  the  performance  of 
their  functions.  The  effects  of  alcohol  on  the  isolated  heart  (p.  259) 
have  indicated  this  with  a  high  degree  of  probability.  For  the  whole 
body  this  fundamentally  important  question  has  repeatedly  been 
the  subject  of  investigations,*  in  which  the  tissue  and  energy  changes 
in  man  and  beast  at  work  and  at  rest  have  been  observed.  In  these 
experiments  the  attempt  has  been  made  to  determine  whether  the 
administration  of  alcohol  results  in  a  sparing  of  other  constituents 
of  the  body,  especially  of  the  carbohydrates  and  fats  and  indirectly 
of  the  proteids. 

Nearly  all  the  authors  who  have  occupied  themselves  with  this  question 
have  concluded  that  alcohol,  which  is  almost  completely  combusted  in  the 
body,  may  replace  equivalent  amounts  of  carbohydrates,  fats,  and  proteids  as  a 
source  of  energy. 

Kassowitz,  in  a  careful  critique  of  these  articles,  has  shown  that  there 
is  still  reason  to  doubt  the  significance  and  interpretation  of  many  of  the 
results  of  such  investigations,  such  as  the  calculations  of  the  amount  of  COZ 
produced,  of  O2  consumed,  and  of  N  excreted,  as  also  of  the  directly  determined 
caloric  balances;  but  his  critique  based  on  such  calculations  can  hardly  be 
maintained  to  be  satisfactory,  in  the  face  of  Durig's  experiments.  Furthermore 
Eassowitz  bases  his  denial  of  any  nutritive  properties  of  alcohol  largely  on 
theoretical  hypothesis,  as  follows.  He  claims  that  the  muscle-cell  is  not  to 
be  compared  with  a  power  machine  run  by  heat  resulting  from  the  combustion 
of  foodstuffs,  but  that,  on  the  contrary,  like  all  living  cells,  the  muscle-cell  is 
a  labile  complex,  which  is  constantly  being  built  up  and  broken  down, 
assimilating  the  nutritive  material  brought  to  it  and  utilizing  it  to  replace  and 
build  up  anew  its  own  protoplasm,  producing  heat  and  performing  work  by 
<;atabolism  of  its  protoplasm  and  not  by  direct  combustion  of  any  sort  of 
fuel  which  may  be  brought  to  it.  As  alcohol  is  not  suitable  material  for 
these  assimilative  anabolic  processes,  it  is  useless,  and  is  combusted  in  a  sense 
outside  of  the  protoplasm  without  utilization  of  the  energy  produced  for  the 
performance  of  work.  It,  therefore,  cannot  serve  the  cell  as  a  source  of  energy 
as  do  the  true  foods,  proteids,  fats,  and  carbohydrates. 

This  argument  against  the  biological  utilization  of  alcohol  can  no  longer 
be  considered  as  pertinent,  since  it  has  been  established  that  alcohol  is  formed 
in  normal  metabolism  as  a  result  of  the  anabolism  of  the  protoplasm. 
Stoklasa's  discovery,  that  animal  and  vegetable  cells  contained  an  enzyme 
which  fermented  carbohydrates  with  formation  of  C02  and  alcohol,  indicated 
with  great  probability  that  this  was  the  case,  although  A.  Harden  and  Maclean 
have  since  then  raised  a  doubt  as  to  the  presence  of  such  enzymes  in  animal 
tissues.  Landsberg  and  Reach,  however,  have  brought  a  direct  proof  of  the 
presence  of  alcohol  in  normal  tissues.  The  latter  author  found  0.0017  per  cent. 
of  free  alcohol  and  small  quantities  of  ethyl  esters  in  rabbits'  muscles,  liver, 
and  brain.  As  alcohol,  therefore,  is  formed  in  the  normal  mechanism — i.e., 
according  to  Kassowitz,  "  biologically " — it  is  no  longer  to  be  doubted  that  its 
combustion  may  be  of  value  to  the  cell.  Whether  the  alcohol  reaches  the  cell 
from  the  outside  or  is  formed  in  it  can  make  no  fundamental  difference. 

Alcohol,  a  Utilizable  Food,  with  Limitations. — In  general  it  may 
be  said  that  alcohol  is  a  food  which  is  utilized  rapidly,  but  that  it 

*  For  the  very  voluminous  literature  bearing  on  this  subject,  see  M. 
Kochmann  u.  W.  Hall,  PflUger's  Archiv.,  vol.  127,  p.  280. 


ALCOHOL  AS  FOOD  433 

is  a  poor  food,  to  be  used  only  in  case  of  need,  for  the  following 
reasons.  Its  potential  energy  is  less  economically  utilized  in  the 
performance  of  work  than  is  that  of  other  food-stuffs,  it  cannot  be 
stored  up  as  a  reserve  to  be  used  as  need  arises,  but,  under  all  cir- 
cumstances, must  be  combusted  at  once,  and,  above  all,  it  is  poisonous. 
A  slight  degree,  although  not  always  a  harmful  one,  of  toxic  action 
is  produced  whenever  alcoholic  beverages  are  used  as  stimulants  or 
as  food.  In  spite  of  this,  it  may  often  happen  that,  when  other  foods 
may  not  be  administered, — as,  for  example,  in  septic  febrile  cases 
or  in  very  sick  diabetics  to  whom  carbohydrates  may  not  be  given, — 
alcohol  may  be  given  with  advantage,  and  may  materially  lessen  the 
results  of  carbohydrate  hunger,  such  as  acidaemia  and  acetonuria 
(Neubauer] . 

Food  and  poison  are  not  necessarily  different  things,  for  peptones 
and  soaps  when  directly  introduced  into  the  blood  are  violent  poisons. 
As,  however,  their  chemical  properties,  their  colloid  nature,  do  not 
permit  this,  they  are  harmless  food-stuffs  when  properly  administered. 
If  alcohol  were  to  reach  in  proper  amounts  only  the  right  place  for  its 
transformation,  it  would  perhaps  be  quite  as  harmless  as  the  higher 
alcohols,  such  as  glycerin.  Alcohol,  however,  differs  from  all  such 
relatively  harmless  substances  in  its  power  of  entering  into  solution 
with  the  lipoids.  This  property  causes  it  to  penetrate  alike  into  all 
cells  and  to  cause  in  them  at  least  temporary  disturbances  of  function. 
That  this  may  lead  to  permanent  serious  results,  especially  to  de- 
generative changes,  is  well  known. 

BIBLIOGRAPHY 

Chauveau:  Compt.  rend.  Acad.  des  sciences,  1901,  vol.  132,  pp.  65,  110. 

Durig:   Piiuger's  Arch.,   1906,  vol.   113,  p.   380. 

Fick,  A.:  Korr.  f.  Schw.  A.,  1896,  No.  14,  p.  445. 

Frey:  Mitt,  aus  klin.  u.  med.  Inst.  d.  Schweiz,  Serie  4,  1896,  No.  1. 

Harden,  A.,  and  Maclean:  Journ.  of  Physiol.,  1911,  vol.  42,  p.  64. 

Hellsten,  A.  F.:  Skand.  Arch.  Phys.,  1907,  vol.  19,  p.  201. 

Joteyko:   Trav.  Solv.,  vol.  6,  p.  431,  1904. 

Joteyko:  Trav.  Solv.,  vol.  6,  p.  447,  here  lit. 

Kassowitz:  Fortschr.  d.  Med.,  1903,  Nos.  4  and  27. 

Kassowitz:  Therap.  Monatsh.,  1908,  Nos.  6  and  7. 

Kochmann,  M.,  u.  W.  Hall:   Pfliiger's  Arch.,   1909,  vol.   127,  p.  280. 

Landsberg:  Ztschr.  f.  phys.  Chemie,  1904,  vol.  41. 

Neubauer,  O.:  Miinchn.  med.  Woch.,   1906,  No.   17. 

Reach:  Biochem.  Ztschr.,  1907,  vol.  3,  p.  326. 

Scheffer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  44. 

Schumburg:   Dubois'   Arch.,    1896,   p.   537. 

Schumburg:   Die   Milit.-arztl.   Ztg.,  August,    1896. 

Stoklasa:  Physiol.  Zentralbl.,  1902,  vol.  16,  p.  712,  and  1903,  vol.  17,  p.  465. 

Verzas :   Pfluger's  Arch.,  1909,  vol.  128,  p.  398. 

Weiland:  Deut.  Arch.  f.  klin.  Med.,  1908,  vol.  92,  p.  223. 

TESTICULAR  EXTRACTS 

At  the  close  of  this  section  a  very  remarkable  action  of  these 
extracts  should  be  mentioned.  This  was  first  noted  by  Brown 
Sequard  and  his  collaborators,  and  has  recently  been  carefully  in- 

28 


434  PHARMACOLOGY  OF  THE  MUSCLES 

vestigated  by  Zoth  and  Pregl.  According  to  these  latter  authors,  the 
subcutaneous  injection  of  Sequardine  (a  glycerin  extract  of  bulls y 
testicles  obtainable  from  Perrottet  &  Cie.,  Geneva)  causes  an  extra- 
ordinary increase  of  the  effect  of  systematic  muscular  exercise. 

Daily  injections  for  one  week  produced  no  effect  on  the  muscular  power  as 
measured  ergographically  or  otherwise,  and  daily  exercises  without  injections 
were  also  without  effect.  Both  together,  however,  caused  a  marked  increase  in 
the  muscular  power,  showing  itself  in  postponement  of  fatigue  objectively  and 
subjectively,  as  well  as  in  an  increase  in  the  benefit  resulting  from  pausing  to 
rest.  In  Zoth's  experiments,  in  which  heavy  dumb-bells  were  used  daily  and 
daily  injections  were  administered,  the  increase  amounted  to  14-20  per  cent, 
of  the  original  performance  after  8,  9,  or  12  days,  while  without  injections 
70  practice  exercises  during  five  weeks  caused  an  increase  of  but  12  per  cent. 
Exercise  plus  injections  resulted  quickly  in  attaining  an  increase  of  power 
which  by  exercise  alone  was  not  attainable.  A  distinct  increase  in  the  cir- 
cumference of  the  upper  arm  also  accompanied  the  increase  in  muscular  power. 

These  extracts  appear  therefore  to  bring  about  a  peculiar  improve- 
ment in  the  assimilative  processes  of  the  muscle-cells. 

BIBLIOGRAPHY 
Zoth  u.  Pregl:  Pfttlger's  Arch.,  1896,  vol.  62,  here  literature,  and  1898,  vol.  69. 


CHAPTER  XIV 
PHARMACOLOGY  OF  THE  BLOOD 

UNDER  pathological  influences  the  blood  may  undergo  both  quan- 
titative and  qualitative  alterations  which  demand  not  only  dietetic 
but  medicinal  treatment. 

EFFECTS  OF  INFUSIONS  ON  THE  BLOOD  VOLUME. — The  most  im- 
portant alteration  of  the  blood  volume,  and  one  which  often  imperils 
life,  is  acute  anaemia,  a  diminution  of  the  blood  volume  resulting 
from  hemorrhage  or  profuse  diarrhoeas  (cholera)  and  affecting  the 
whole  vascular  system,  or  in  case  of  "  bleeding  into  the  abdominal 
vessels"  as  occurs  in  paralysis  of  the  splanchnics,  affecting  chiefly 
the  vitally  important  vascular  systems  of  the  heart  and  central 
nervous  system.  In  such  cases,  merely  increasing  the  volume  of  the 
circulating  fluid  by  diluting  the  blood  by  intravenous — or  in  less 
urgent  cases  by  subcutaneous  [or  rectal. — TE.] — administration  of 
physiological  saline  solution  (0.9  per  cent.  NaCl)  may  be  a  life- 
saving  measure.  In  such  case  the  chief  indication  is  to  bring  about 
more  favorable  conditions  for  the  cardiac  function  (p.  319).  In 
addition,  according  to  Ott,  the  saline  infusion  actively  stimulates 
the  regeneration  of  the  red  cells.  (See  also  Zachrisson.} 

A  CONDENSATION  OF  THE  BLOOD  may,  on  the  other  hand,  be  of 
value  under  certain  conditions,  as,  for  example,  for  the  purpose  of 
favoring  the  absorption  of  pleural  or  peritoneal  exudates  or  of 
03dema.  This  may  be  accomplished  by  bringing  about  the  loss  of 
large  amounts  of  water  through  the  skin,  kidneys,  or  intestine.  (See 
discussions  of  diaphoresis,  diuresis,  and  catharsis.) 

The  most  important  anomalies  of  the  blood  are  the  alterations  in 
the  number  and  quality  of  the  red  and  white  cells  which  occur  in 
chlorosis  and  other  anaemias.  In  chlorosis  the  number  of  the  red  cells 
and  their  hemoglobin  content  are  markedly  diminished.  The  indica- 
tion is,  therefore,  to  bring  about  a  greater  production  of  normal 
healthy  cells,  for  which  indication  iron  has  been  for  centuries  con- 
sidered the  most  valuable  drug. 

IRON 

Although  originally  the  administration  of  iron  in  conditions  of 
weakness,  anaemia,  and  chlorosis  was  crudely  empiric  or  else  based 
on  mystic  ideas,  it  obtained  a  scientific  foundation  as  early  as  1746, 
when  Menghinis  discovered  that  iron  was  a  characteristic  constituent 
of  the  blood,  existing  "  in  sola  sanguinis  parte  globulari. "  He  also 
found  that  the  administration  of  food  containing  iron  increased  the 
iron  content  of  the  blood.  These  observations,  later  confirmed  by 

435 


436 


PHARMACOLOGY  OF  THE  BLOOD 


numerous  observers,  were  supplemented  in  1830  by  Fodisch,  who 
found  the  iron  content  of  the  blood  of  chlorotics  to  be  materially  di- 
minished, and  finally  by  Andral,  Gavaret,  and  Delafond  (1842),  who 
demonstrated  an  increase  in  the  number  of  the  red  cells  after  admin- 
istration of  iron.  These  quantitative  observations  have  since  then 
been  repeatedly  confirmed. 

Older  Theories  as  to  Action  of  Iron. — From  such  observations  it 
appeared  that  a  scientifically  founded  and  satisfactory  theory  for 
the  effects  of  iron  therapy  had  been  obtained;  that  the  iron  which 
was  administered  was  utilized  in  the  formation  of  haemoglobin. 
However,  before  long  the  correctness  of  this  view  was  seriously  ques- 
tioned, chiefly  for  two  reasons.  Many  clinicians  cast  doubt  on  the 
value  of  iron  in  the  treatment  of  chlorosis,  or  assumed  that  the 
repeatedly  demonstrated  increase  in  the  iron  content,  or  in  the 
haemoglobin  or  in  the  number  of  erythrocytes  of  blood,  which  followed 
the  administration  of  iron,  even  when  other  therapeutic  procedures 
were  not  employed,  was  possibly  not  a  real  but  only  an  apparent  in- 
crease. As  a  matter  of  fact,  up  to  this  time  the  quantitative  deter- 
minations of  iron,  haemoglobin,  and  red  cells  had  been  made  only 
in  a  given  unit  of  blood,  and,  therefore,  any  increase  found  might 
be  only  a  relative  one  due  to  concentration  of  the  blood. 


Red  cells  in  mill- 
ions per  cu.  mm. 


9 
£ 

7 
f 

1 

^N 

18 

kg.  a 

00 

/ 

\ 

\ 

/ 

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0     %***/*   /«*  2*  £&*                          /*           £*           3* 

Fia.  51. — Graphic  representation  of  variation  in  the  number  of  red  cells  in  the  cu. 
mm.  as  a  result  of  concentration  and  of  dilution  of  the  blood. 

Marked  variations  in  the  concentration  of  the  blood  actually  do  occur 
under  various  conditions,  either  as  a  result  of  furnishing  water  to  the  tissues, 
especially  to  the  glands,  or  as  a  result  of  vasoconstriction.  The  effect  on  the 
concentration  of  the  blood  exerted  by  the  digestion  of  dry  food — i.e.,  by  the 
pouring  out  of  the  digestive  juices  into  the  alimentary  canal — is  well  shown 
by  Buntzen'a  experiments  on  dogs  (Fig.  51).  Here  feeding  with  bread  in- 
creases the  number  of  red  cells  in  the  unit  volume  by  10-20  per  cent.  In 
long-continued  fasting  also  the  relative  number  of  red  cells  is  markedly  in- 
creased, for  under  these  conditions  the  blood  loses  much  more  fluid  from  its 
plasma  than  from  its  cells  (Fig.  52).  This  last  observation  has  been  con- 
firmed in  human  subjects  by  Andreesen. 

The  effect  of  varying  vascular  tone  is  quite  as  well  pronounced,  with 
increased  tone  fluid  passing  from  the  blood  to  the  tissues  and  the  relative 
number  of  red  cells  rising,  but  falling  with  diminished  tone.  The  vascular 
tone,  as  is  well  known,  may  be  influenced  through  the  vasomotof  centres  by 


IRON 


437 


various  means.     For  example,   it  is  diminished  by  alcohol    (Fig.  53)    and  in- 
creased by  the  action  of  cold, — e.g.,  by  cold  baths    ( Tonnissen ) . 

However,  not  every  augmentation  of  arterial  tone  results  in  the  passing 
out  of  plasma  through  the  capillary  wall,  for,  if  the  increased  tone  affects 
chiefly  the  smaller  arteries  and  arterioles,  the  capillaries,  being  below  the  con- 
traction, contain  but  moderate  amounts  of  blood  under  low  pressure,  and 
therefore  need  not  squeeze  any  plasma  into  the  tissues.  If,  however,  the  tonic 


Red  ce 
9 

8 

7 
6 

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9.0  kilo 
8.t 
8.e 

8.4 

3.t 
8.0 
7.t 
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s- 

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\ 

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3 

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FIG.  52. — Influence  of  fasting  on  the  concentration  of  the  blood. 

contraction  affects  principally  the  most  peripheral  capillaries  or  a  portion  of 
tiiem  (epinephrin  intravenously),  the  blood  stagnates  in  the  less-contracted 
portions  of  the  capillaries  and  arterioles  lying  above  the  constriction, 
and  is  there  subjected  to  a  high  pressure  which  squeezes  out  the  plasma  fluid. 
In  a  similar  fashion  plasma  is  expressed  in  large  quantities  in  artificial  plethora, 
such  as  results  from  infusion  of  blood,  although  the  vessels  are  not  constricted. 
Magnus  found  that  from  20  to  40  per  cent,  of  the  infused  fluid  was  expressed 


Red  cells 
in  millions 


j 

lee 

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m 

in 

of 

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*           » 

260  c.c.  u 
daily 

£50  c.c.  wine 
daily 

£*/**&* 
FIG.  53. — Influence  of  alcohol  on  concentration  of  blood  (Andreesen). 

into  the  tissues  3-5  minutes  after  infusion  of  homogeneous  blood  in  amounts 
corresponding  to  20-50  per  cent,  of  their  original  blood  volume.  In  such  cases 
the  blood  was  correspondingly  concentrated. 

One  might  be  tempted  to  explain  the  variations  in  the  relative  number  of 
blood-cells  as  being  due  not  to  a  passing  in  and  out  of  plasma  through  the  walls 
of  the  finest  capillaries,  but  by  assuming  an  emigration  of  cells  back  and  forth 
from  reserves  of  concentrated  blood,  perhaps  from  the  wide  mesenteric  veins, 
so  that  these  variations  would  be  explained  as  due  only  to  an  alteration,  in 
the  distribution  of  blood  containing  varying  numbers  of  red  cells. 

However,  there  are  no  grounds  for  assuming  the  existence  of  reserves  of 
blood-cells,  for  the  concentration  of  the  red  cells  is  almost  equal  in  all  veins  and 
'  ;ries  (Hess,  Erb,  Donath). 


438  PHARMACOLOGY  OF  THE  BLOOD 

These  variations,  however,  which  depend  on  administration  of  food  or  loss 
of  water  are  not  lasting,  and  cannot  in  any  way  explain  the  constant  increase 
in  the  number  of  erythrocytes  which  results  from  the  successful  treatment  of 
chlorosis. 

Another  series  of  objections  to  the  view  that  iron  medicinally 
administered  is  utilized  for  the  formation  of  haemoglobin  base  them- 
selves on  the  physiology  and  toxicology  of  iron. 

IRON  IN  FOOD-STUFFS. — In  all  food-stuffs,  vegetable  as  well  as 
animal,  iron  is  present  in  assimilable  form  and  in  amounts  sufficient  to 
supply  the  increasing  needs  of  the  growing  body  and  to  compensate 
for  the  amounts  lost  by  adult  animals  in  the  faeces  and  urine.  It  is 
present  in  these  food-stuffs  not  in  the  form  of  salts,  in  which  it 
may  be  directly  demonstrated  by  ordinary  reagents,  but  in  organic 
combinations,  probably  in  combination  with  nucleoproteids  or  similar 
substances.  In  this  form  the  iron  is  without  doubt  absorbed  and  pro- 
vides the  body  with  the  material  for  the  formation  and  maintenance 
of  its  ferruginous  constituents.  With  the  exception  of  milk,  rice, 
white  bread,  and  many  fruits,  the  substances  used  as  food  contain  iron 
in  such  quantity  that  an  ordinary  mixed  diet  supplies  enough  iron 
for  ordinary  needs. 

Iron  Balance  during  Administration  of  Inorganic  Iron. — If  this 
be  so,  why  not  give  anaemic  cases  an  ample  diet  of  food  which  is  rich 
in  iron,  in  place  of  administering  iron  salts,  of  which,  to  begin  with, 
it  was  not  known  whether  they  were  absorbed  at  all  or,  if  absorbed, 
in  what  amounts?  Formerly,  in  fact,  it  appeared  very  doubtful 
whether  iron  salts  were  absorbed  at  all,  for  in  the  human  urine  under 
normal  conditions  1-2  mg.  of  iron  are  excreted  daily,  and  after  the 
administration  of  iron  salts  this  amount  is  not  increased,  although  in 
the  case  of  almost  all  substances,  which  are  absorbed  and  reach  the 
circulation,  at  least  a  part  is  excreted  in  the  urine  (Gottlieb}.  As  a 
matter  of  fact,  almost  all  the  iron  thus  administered  may  be  re- 
covered from  the  fgeces  (Marfori,  Kletzinski,  Hamburger"). 

This  fact,  however,  was  not  a  valid  argument  against  the  absorba- 
bility of  iron  combinations,  for  Wild's  exact  quantitative  determina- 
tions of  the  iron  content  of  different  portions  of  the  intestine  have 
demonstrated  that,  of  the  iron  contained  in  food  which  is  certainly 
absorbed,  any  superfluous  amount  is  excreted  again  in  the  lower 
bowel.  Moreover,  ordinary  salts  of  iron  when  administered  sub- 
cutaneously  are  excreted  not  by  the  kidneys,  but  exclusively  by  the 
intestine,  as  has  been  shown  by  Gottlieb.  As  the  bile  contains  only 
traces  of  iron  (Novi),  this  excretion  must  be  the  work  of  the  intestinal 
glands.  In  view  of  these  facts,  it  was  not  possible  to  deny  that,  when 
salts  of  iron  were  administered,  they  were  absorbed  in  the  upper 
portion  and  after  circulating  in  the  body  were  excreted  in  the  lower 
portion  of  the  intestine. 

Finally,  still  another  objection  was  raised  by  those  doubting  the 
value  of  iron  medication,  on  the  ground  that,  if  corrosive  effects  be 


IRON  439 

excluded,  neither  chronic  nor  acute  poisoning  followed  the  oral  ad- 
ministration of  iron,  although  iron  salts  when  administered  sub- 
cutaneously  or  intravenously  had  proven  themselves  extremely  toxic, 
similarly  to  arsenic  (Meyer  and  Williams). 

It  was,  therefore,  concluded  that,  as  ordinary  food-stuffs  contain 
sufficient  iron,  and  as  the  medicinal  preparations  of  iron  are  probably 
not  absorbed  and  therefore  cannot  be  utilized,  the  favorable  effects 
of  the  administration  of  these  preparations  must  be  explained  by 
local  action  in  the  alimentary  tract,  especially  by  a  protection  of  the 
iron  in  the  food  from  alteration  by  substances  present  in  the  bowel 
which  have  a  strong  affinity  for  iron,  such,  for  example,  as  the 
sulphides. 

These  conclusions  have,  however,  all  been  shown  to  be  incorrect. 
The  lack  of  toxicity  of  iron  administered  by  mouth  in  no  way  in- 
dicates that  it  is  not  absorbed,  for  many  substances, — e.g.,  potassium 
salts,  curare,  and  others, — although  extremely  toxic  when  administered 
intravenously  or  subcutaneously,  are  absorbed  in  large  amounts  from 
the  intestine  without  producing  any  toxic  effects.  This  is  in  many 
cases  due  to  a  protective  influence  of  the  liver,  which  is  the  first  organ 
reached  by  these  substances  after  they  are  absorbed,  and  which  either 
renders  them  harmless  by  chemical  means,  or  retains  them  for  a 
time  (Eothberger) ,  so  that  their  excretion  by  the  kidney  or  intestine 
keeps  pace  with  their  arrival  in  the  blood  and  thus  prevents  the 
attainment  of  that  concentration  in  the  blood  necessary  to  cause 
toxic  effects.  This  is  also  the  case  with  the  salts  of  iron. 

PROOFS  OF  THE  ABSORPTION  OF  INORGANIC  IRON  SALTS. — In  ad- 
dition, it  has  been  definitely  proven  that  inorganic  salts  of  iron  may 
be  absorbed  in  the  absence  of  any  lesions  of  the  intestinal  mucous 
membrane.  That  this  occurs  chiefly  in  the  small  intestine  has  been 
demonstrated  both  by  microchemical  examination  of  the  intestinal 
mucous  membrane  (MacCallum,  Quincke,  Gaule)  as  also  by  the 
chemical  demonstration  of  the  presence  of  iron  in  the  lymph  from 
the  thoracic  duct  45  minutes  after  the  introduction  into  the  stomach 
of  a  0.06  per  cent,  solution  of  ferric  chloride  (Gaule),  and  also  by 
comparison  of  the  amounts  of  iron  administered  to  men  and  animals 
and  the  exactly  determined  amounts  excreted  by  the  intestine  and 
the  kidney  (Hofmann). 

ITS  UTILIZATION  IN  THE  FORMATION  OF  HAEMOGLOBIN. — Finally, 
Kunkel  has  shown  that  iron  salts  are  not  only  absorbed,  but  that  they 
are  stored  up  in  the  body  for  future  use  and  are  used  in  the  synthesis 
of  haemoglobin.  This  author  repeatedly  bled  two  puppies  as  nearly 
alike  as  possible  and  thus  rendered  them  anaemic  and  impoverished  in 
iron,  feeding  both  animals  exclusively  on  milk,  which  contains  very 
little  iron,  except  that  one  of  the  subjects  received  daily  about  6  mg 
of  Fe  in  the  form  of  Liq.  ferri  albuminati.  After  six  weeks  one  dog 
was  extremely  anaemic,  its  blood  containing  only  0.019  per  cent. 


440 


PHARMACOLOGY  OF  THE  BLOOD 


Fe203,  and  the  whole  liver  only  0.004  gin.  Fe2O3,  while  the  other  dog, 
which  had  received  the  iron,  was  of  normal  strength,  its  blood  contain- 
ing 0.035  per  cent.  Fe203  and  the  liver  0.032  gm.  Fe203. 

These  results  were  confirmed  by  Cloetta  in  nine  young  puppies, 
which  were  subjected  to  experiment  immediately  after  weaning.  All 
of  them  received  no  food  except  milk,  but  six  received  in  addition 
daily  doses  of  35  mg.  of  iron,  as  lactate  of  iron  or  as  ferratin,  a 
proteid  containing  iron  in  combination.  The  hemoglobin  was  esti- 
mated at  various  intervals,  with  the  results  given  in  the  table  below. 
Haemoglobin  in  Growing  Puppies  Fed  on  Milk. 


Group  II,  milk  and 

Group  III,  milk 

Hgb.  expressed  in 
percentages  of  normal 

Group  I,  milk  alone 

lactate  of  iron,  35  mg. 
Fe  daily 

and  ferratin,  35  mg. 
Fe  daily 

Hgb.  content 

1 

2 

3 

1 

2 

3 

1 

2 

3 

After    4  weeks.  .  .  . 

78 

81 

51 

95 

97 

94 

96 

94 

94 

After    7  weeks.  .  .  . 

66 

67 

31 

92 

95 

93 

95 

93 

91 

After    9  weeks.  .  .  . 

45 

40 

28 

87 

94 

95 

98 

94 

90 

After  12  weeks.  .  .  . 

35 

24 

99 

94 

99 

93 

Kunkel's  results  have  been  completely  confirmed  by  Abderhalden 
working  in  Bunge's  laboratory.  In  a  large  series  of  parallel  observa- 
tions, Abderhalden  fed  to  young  puppies  as  soon  as  weaned  and  to 
new-born  guinea-pigs  normal  diet,  or  a  diet  containing  little  iron,  and 
both  of  these  diets  with  or  without  addition  of  iron,  using  in  some 
cases  salts  of  iron,  and  in  others  organic  iron  preparations  such  as 
haematin  or  similar  substances.  He  found  that  all  the  iron  prepara- 
tions, when  added  to  the  diet  containing  little  iron,  were  absorbed 
and  used  for  the  formation  of  haemoglobin.  "When,  however,  iron 
preparations  were  added  to  the  normal  diet  which  contained  iron, 
remarkable  difference  was  noted  between  the  animals  which  had 
received  inorganic  iron  and  those  which  had  received  organic  iron. 
In  the  latter  group  no  recognizable  differences  from  the  normal  con- 
trols were  noted,  but  the  addition  of  inorganic  iron  preparations  to 
the  normal  diet  markedly  stimulated  both  the  formation  of  haemoglobin 
and  the  gain  in  weight.  These  effects,  however,  were  produced  only 
for  a  certain  length  of  time,  after  which  habituation  appeared  to 
develop. 

By  these  experiments,  which  have  been  substantially  confirmed 
elsewhere  (Tartakowsky) ,  it  may  be  considered  as  proven  that  the 
salts  of  iron  may  not  only  be  utilized  as  material  for  the  synthesis 
of  haemoglobin,  but  may  also  exert  a  specific  action  on  the  blood- 
forming  organs  (bone-marrow)  and  probably  on  the  processes  of 
growth  and  metabolism  in  other  tissues.  This  latter  is  indicated  by 
Eomberg's  observation,  that  in  chlorosis  the  tissues  contain  abnormally 
large  amounts  of  water  and  that  this  disappears  under  the  influence 
of  iron. 


IRON  441 

Finally,  the  histological  findings  in  the  bone-marrow  agree  with 
this  assumption  of  a  stimulation  of  the  blood-forming  organs  by  iron. 
According  to  Fr.  Mutter,  the  bone-marrow  of  animals  artificially 
rendered  anaemic  contains  more  nucleated  red  cells  when  iron  is  ad- 
ministered than  is  the  case  when  no  iron  is  added  to  the  normal  diet. 

It  must  therefore  be  assumed  that  the  effects  of  iron  in  chlorosis 
are  due  to  two  factors :  first,  the  utilization  of  the  iron  in  the  synthesis- 
of  haemoglobin  and  in  the  formation  of  reserve  substances  which  are 
rich  in  iron  and  are  stored  up  in  the  liver;  and,  second,  a  specific 
stimulation  of  the  cells  which  form  haemoglobin,  as  taught  by  Trous- 
seau and  as  reaffirmed  by  Harnack  and  v.  Noorden. 

Relative  Inefficiency  of  Organic  Iron  Preparations. — On  account 
of  the  difficulty  with  which  they  are  decomposed,  haemoglobin  deriva- 
tives produce  this  second  specific  and  therapeutically  very  important 
effect  either  not  at  all  or  in  only  a  slight  degree.  Apparently  they 
appear  to  be  utilized  only  in  the  same  way  as  the  organic  iron 
present  in  food-stuffs.  [The  same,  in  all  probability,  holds  true  for 
all  of  the  high-priced  and  much-advertised  preparations  containing 
iron  in  organic  combination.  Although  their  vendors  claim  for  them 
extraordinary  therapeutic  powers,  they  are  without  exception  in  all 
probability  less  effective  than  the  old  simple  inorganic  preparations. 
The  only  justifiable  claim  which  may  be  made  for  them  is  that  they 
do  not  produce  the  same  local  effects  on  the  mucous  membrane  as  do 
some  of  the  inorganic  preparations.  This  advantage  is,  however, 
purchased  at  the  cost  of  therapeutic  efficiency. — TR.] 

This  power  possessed  by  iron,  of  stimulating  or  causing  metabolism 
and  growth,  is  only  a  specific  instance  of  its  general  importance  for 
all  vital  processes.  It  is  a  constant  and  integral  constituent  not  only 
of  the  lower  animals  (Crustaceae,  etc.),  where  it  is  present  as  ferrin, 
but  it  is  necessary  for  the  growth  of  the  fungi  (Molisch)  and  of  the 
higher  plants,  in  which  latter  it  is  necessary  for  the  production  of 
chlorophyll,  although  this  contains  no  iron. 

As  exact  experimentation  and  clinical  experience  both  indicate 
that  the  action  of  the  iron  salts  is  materially  different — at  the  least 
is  quantitatively  different — from  that  of  the  iron  contained  in  food- 
stuffs, a  rational  foundation  has  been  gained  for  the  administration 
of  iron  in  chlorosis  in  addition  to  providing  for  a  diet  rich  in  iron. 

Moreover,  the  ordinary  diet  of  man  is  by  no  means  very  rich  in 
iron.  Stockman's  figures  are  as  follows:  Ordinary  diet  8-11  mg.  per 
diem;  insufficient  diets,  especially  when  appetite  is  poor,  6-8  mg., 
and  at  times  as  low  as  4  mg.  In  the  daily  output  of  faeces  and  urine 
of  four  exactly  observed  cases,  he  found  that  the  iron  approximately 
equalled  the  amount  ingested.  During  fasting  an  adult  man  excretes 
8-10  mg.  of  iron,  for  the  celebrated  faster  Cetti  the  mean  figure  for 
the  iron  in  the  faeces  was  7  mg.,  and  for  Breithaupt  8  mg.  According 
to  these  figures,  the  normal  human  diet  contains  enough  iron  to  replace 


442  PHARMACOLOGY  OF  THE  BLOOD 

the  unavoidable  loss  through  wear  and  tear,  but  hardly  enough  to 
overcome  any  deficiency  resulting  from  an  existing  disease.  The  im- 
portance of  these  facts  is  self-evident. 

COMPARATIVE  VALUE  OF  THE  DIFFERENT  IRON  PREPARATIONS. — • 
From  what  has  gone  before,  it  may  be  concluded  that,  for  purposes 
of  practice,  all  iron  preparations  are  in  principle  of  equal  value, 
with  the  exception  of  haemoglobin,  its  derivatives,  and  similar  organic 
combinations  which  in  their  behavior  appear  to  resemble  the  iron 
contained  in  food.  This  has  been  confirmed  by  clinical  experiments 
conducted  for  the  purpose  of  investigating  this  assumption. 

Behavior  in  the  Alimentary  Canal. — However,  the  different  prep- 
arations differ  quite  materially  in  respect  to  their  local  actions  on 
the  mucous  membrane  of  the  alimentary  canal  and  the  rapidity  and 
completeness  with  which  they  are  absorbed.  All  the  simple  salts  of 
iron,  which  possess  an  acid  reaction,  exert  an  astringent  or  corrosive 
action  on  mucous  membranes,  which  varies  in  its  intensity  with  the 
amount  and  the  concentration.  If  the  stomach  be  especially  suscep- 
tible, this  may  be  the  cause  of  digestive  disturbances  or  loss  of  ap- 
petite, and  especially  of  constipation.  Examples  of  such  preparations 
are  Ferrum  reductum,  converted  into  the  chloride  by  the  gastric 
juice,  Ferri  carbonas  saecharatus,  and  the  lactate,  citrate,  and  malate 
of  iron.  By  addition  of  alkali  the  acid  reaction  of  the  iron  salts 
and  their  astringency  are  lessened.  This  accounts  for  the  fact  that 
such  preparations  as  Blaud's  pills  are  usually  so  well  borne.  The 
same  is  true  of  the  chalybeate  waters,  which  usually  contain  alkaline 
carbonates.  Their  great  dilution  also  renders  their  local  action  prac- 
tically negligible.  Preparations  containing  iron  in  colloidal  form 
or  in  combination  with  proteid,  from  which  it  is  split  off  only  gradu- 
ally, are  still  less  likely  to  produce  undesirable  local  effects.  Dialyzed 
iron  and  the  albuminate  or  peptonate  of  iron  are  examples  of  such 
preparations. 

ORGANIC  IRON  PREPARATIONS. — Ferratin  (acid  albuminate  of  iron) 
containing  3  per  cent.  Fe,  carniferrin  (phosphocarnate  of  iron)  20 
per  cent.  Fe,  and  triferrin  (paranucleinate  of  iron)  30  per  cent.  Fe, 
all  contain  their  iron  in  very  firm  combination,  and,  like  the  various 
commercial  preparations,  which  contain  haematin,  produce  no  local 
effects,  but  also  do  not  exert  a  specific  stimulant  effect  after  ab- 
sorption. 

In  any  iron  preparations,  ionizable  iron  gives  with  hsematoxylin  a  dark- 
violet  color-reaction.  This  may  be  used  for  determining  whether  or  not  the  iron 
be  present  in  available  form  (Macallum). 

Ferric  chloride  is  not  only  an  astringent  and  irritant  but  also 
a  coagulant  for  blood  and  possesses  slight  antiseptic  powers. 

TOXICOLOGY. — Actual  poisoning  by  iron  can  occur  only  when  iron 
salts  are  administered  parenterally, — i.e.,  subcutaneously  or  intraven- 
ously. 


MANGANESE  AND  ARSENIC  443 

In  rabbits,  dogs,  and  cats,  30  nig.  per  kilo,  body  weight  when  thus  ad- 
listered  cause  paralysis  and  death.  If  the  amount  administered  is  so  large 
that  not  all  the  iron  can  combine  with  the  proteids  of  the  blood,  the  free  iron 
salts  damage  the  kidney  epithelium  and  are  excreted  by  this  organ,  but  such 
harmful  effects  never  result  from  the  subcutaneous  administration  of  iron,  some- 
times employed  in  therapeusis  (Quincke,  Lepine).  [One  occasionally  meets 
with  statements  that  iron  may  in  this  way  be  harmful  in  cases  of  nephritis,  but 
this  view  is  in  absolute  contradiction  to  both  experimental  and  clinical  evi- 
dence.— TB.] 

BIBLIOGRAPHY 

Abderhalden:   Ztschr.  f.  Biologic,  1900,  vol.  39. 
Andreesen:   Diss.,  Dorpat,  1883. 

Buntzen:   Om  Erniiringen  og  Blodtabets,  etc.,  Kjobenhavn,  1879. 
Cloetta:   Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38. 
Erb:   Deut.  Arch.  f.  klin.  Med.,  1907,  vol.  88,  p.  36. 
Gaule:   D.  med.  Woch.,  1896,  vol.  22,  Nos.  19  and  24. 
Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  vol.  26. 
Gottlieb:   Zeitschr.  f.  physiol.  Chem.,  1891,  vol.  15. 
Hamburger:   Zeitschr.  f.  physiol.  Chem.,  1878,  vol.  2;   1880,  vol.  4. 
Harnack:   Lehrb.,   1883,  p.  459. 

Hess:  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  79,  p.  128. 
Hofmann:   Virchow's  Arch.,  1898,  vol.  151. 
Kletzinski:   Z.  Ges.  d.  Aerzte,  Wien.,  1854,  vol.  10,  p.  2. 
Kunkel:     Pfluger's  Arch.,  1895,  vol.  61. 
Lepine:  Sem.  med.,  1897,  vol.  17,  p.  25. 
Macallum:   Journ.  of  Phys.,  1894,  vol.  16;  1897. 
Magnus:   Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  45,  p.  210. 
Marfori:   Arch.  f.  exp.  Path.  u.  Pharm.,   1892,  vol.  29. 
Meyer  u.  Williams:  Arch.  f.  exp.  Path.  u.  Pharm.,  1881,  vol.  13. 
Molisch:   Ber.  Wien.  Akad.  Wiss.,  1894,  vol.  103. 
Miiller,  Fr.:  Virchow's  Arch.,  1901,  vol.  164. 
Noorden:   Berl.  klin.  Woch.,   1895. 
Novi:  Ann.  di  chim.  e  di  farm.,  1890,  vol.  9. 
Ott:   Virchow's  Arch.,  1883,  vol.  93,  p.  114. 
Quincke:   Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  37. 
Romberg:   Berl.  klin.  Woch.,  1897,  No.  25. 

Rothberger  u.  Winterberg:  Arch,  intern,  de  Pharmacodynamie,  1905,  here  litera- 
ture. 

Stockman:   Journal  of  Phys.,  vol.  18,  p.  484,  1895. 
Tartakowsky:   Pfluger's  Arch.,    1904,  vols.    101   and   102. 
Tonnissen:   Diss.,  Erlangen,  1881. 

Trousseau:   Clinique  medic.,  Paris,  1868,  vol.  3,  p.  515. 
Virchow's  Arch.,  1893,  vol.  131,  Suppl. 
Zachrisson,  F. :  Upsala  Lak.  Ferh.  N.  F.,  1900,  vol.  5,  p.  179. 

MANGANESE 

Nothing  certain  is  known  concerning  the  influence  on  the  blood 
exerted  by  this  metal,  but  Hannon*  claimed  to  have  cured  certain 
cases  of  chlorosis*  by  its  use,  while  other  authors,  among  them 
Cervello,  have  made  similar  claims  for  lead  and  for  copper. 

BIBLIOGRAPHY 
Cervello  e  Barabini:  Sul  potere  ematogeno  dei  metalli  pesanti,  Palermo,  1894. 

ARSENIC 

It  appears  to  be  well  established  that  arsenic  exerts  an  action, 
very  similar  to  that  of  iron,  on  the  haematopoietic  organs.  This  is 

*  Hannon  attributed  the  good  effects  obtained  by  this  drug  to  its  power 
of  protecting  the  food  iron  from  the  sulphides  present  in  the  intestine. 


444 


PHARMACOLOGY  OF  THE  BLOOD 


indicated  not  only  by  clinical  evidence,  but  also  by  Bettmann's  and 
Stockmann's  findings  in  the  bone-marrow  of  animals  treated  with 
arsenic.  Thus  far  there  is  no  scientific  foundation  for  the  use  of 
arsenic  in  pernicious  anaemia,  leukaemia,  and  pseudoleuksemia. 

HIGH   ALTITUDES 

A  limitation  of  the  oxygen  supply  affects  the  haematopoietic  organs 
much  as  does  iron  or  arsenic.  It  is  well  known  that  hemorrhage  is 
followed  by  marked  activity  of  the  functions  of  the  bone-marrow  and 
by  rapid  regeneration  of  the  blood.  In  fact,  bloodletting  has  been  em- 
ployed in  chlorosis  as  a  means  of  exciting  an  apparently  sluggish  bone- 
marrow  to  greater  activity.  This,  however,  can  be  accomplished  in 
a  less  harmful  manner  by  cutting  down  the  oxygen  in  the  inspired 
air. 

As  early  as  1877,  Paul  Bert  expressed  the  opinion  that  in  high 
altitudes  the  number  of  the  red  cells  and  the  haemoglobin  must  be 
increased  in  human  beings  or  animals  in  order  to  make  it  possible 
for  them  to  obtain  sufficient  oxygen  from  the  rarefied  air.  Viault 
in  1890  confirmed  this  view  completely  by  observations  made  on  him- 
self and  a  companion  during  a  three  weeks'  stay  at  an  altitude  of 
over  4000  metres.  He  found  the  red  cells  increased  from  5  to  7%  or  8 
million  per  cu.  mm.  Analogous  observations  have  since  then  been 
made  by  numerous  others,  especially  by  Egger  and  by  Miescher  and  his 
pupils  (see  Fig.  54). 

Further  investigations  have  shown  that  this  result  is  due  to  the 
diminution  of  the  oxygen  in  the  air,  for  the  same  increase  in  the 
number  of  the  erythrocytes  results  from  long-continued  breathing  of 
rarefied  air  (Schaumann),  or  air  from  which  part  of  the  oxygen  has 
been  removed  (Sellier). 

For  a  time  it  was  uncertain  whether  this  increase  of  the  red  cells 
was  relative  or  absolute, — i.e.,  whether  the  blood  on  account  of  loss 
of  plasma  appeared  to  contain  more  cells  or  whether  the  amount  of 


Author 

Animal 

Height 
in  m. 

Hcemogl. 
per  kg. 

Air 
diluted  to 
correspond 
with  alti- 
tude of  — 

Hsemogl. 
per  kg. 

Diff  .  in 
per  cent. 

Jaquct  u.  Suter  
Jaquet  

Rabbit 
Rabbit 

280 
280 

5.39 

5  50 

1800  m. 
1600m 

6.59 
6  73 

+23.0 
-j-20  0 

Abderhalden  

Rabbit 

280 

7  99 

1800  m. 

9  32 

+  16  6 

Abderhalden  

Rat 

280 

8  92 

1800m. 

10  62 

+  19  0 

Zuntz  

Dog 

400 

10  78 

2150m 

13  00 

+20  0 

plasma  remained  constant  while  abnormally  large  numbers  of  red 
cells  were  produced.  This  was  settled  by  determining  the  total 
haemoglobin  content  of  animals  which  had  been  kept  in  atmospheres 
containing  different  amounts  of  oxygen,  due  allowance  being  .made  for 


HIGH  ALTITUDES 


445 


Red  cells 
in  millions 


X 


Rabbit 


A 


V 


B^el    * Serneur 


\ 


5  weeks 


Red  cells 
in  millions 


Man 


\ 


266m 


Arosa 


ff    weeks 


Red  cells 
in  millions 


Man 


z 


Serneus    3&5m. 


week* 


FIG.  54.—  Effect  of  various  altitudes  on  the  number  of  the  erythroeytes. 


446  PHARMACOLOGY  OF  THE  BLOOD 

variations  in  body  weight.  The  results  of  such  investigation  as  shown 
in  the  preceding  figures  demonstrate  with  certainty  an  actual  increase 
in  the  number  of  the  red  cells.  This  is  also  indicated  by  the  his- 
tological  examination  of  the  blood  and  bone-marrow  of  the  animals 
kept  at  high  altitudes,  which  demonstrate  the  presence  of  numerous 
normoblasts  in  the  blood,  and  by  the  redness  of  the  bone-marrow. 

Recently  Douglas,  using  Haldane's  method  for  determining  the  total  haemo- 
globin, questions  these  conclusions,  but  this  method,  according  to  Dreyer  and 
Ray,  is  not  reliable,  and  therefore  his  objections  cannot  be  considered  as  proven. 

This  increased  production  of  blood-cells  and  haemoglobin  under 
the  influence  of  diminished  oxygen  tension, — i.e.,  of  very  slightly  de- 
ficient supply  of  oxygen — is  to  be  considered  as  an  unusually  delicate 
compensatory  and  regulative  reaction  of  the  haemoglobin-producing 
organs,  especially  the  bone-marrow. 

This  new  formation  of  red  cells  is,  however,  not  demonstrable  until 
the  rarefied  air  has  been  acting  on  the  subject  for  several  days,  but 
the  number  of  cells  to  the  cu.  mm.  is  at  once  distinctly  increased,  as 
a  result  of  a  temporary  concentration  of  the  blood  in  the  cutaneous 
vessels,  due  probably  to  an  alteration  in  the  distribution  of  the  blood 
throughout  the  body. 

BIBLIOGRAPHY 

Bert,  Paul :   Sur  la  pression  barom6trique. 

Boycott  and  Douglas:  Journ.  Path,  and  Bacter.,  1909,  vol.  13,  p.  256. 

Douglas,  Gordon:  Journ.  of  Physiol.,  1910,  vol.  40,  p.  471. 

Dreyer  and  Ray:  Phil.  Transact.  R.  Soc.,  London,  1910,  vol.  201,  p.  133,  ser.  B. 

Egger,  Miescher  u.  s.  Schiller:   Korr.  f.  schweiz,  Aerzte,  1893,  No.  24. 

Grehant  et  Quinquaud:  J.  d.  1'anat.  et  phys.,  1882,  vol.  18,  p.  564. 

Jaquet:   Ueber  d.  physiol.  Wirkung  d.  Hohenklimas,  Basel,   1904,  literature. 

Schaumann  u.  Rosenquist:   Z.  f.  klin.  Med.,  1898,  vol.  35. 

Sellier:  These,  Bordeaux,  1895. 

Zuntz,  Loewi:  Miiller  u.  Gaspari,  1906,  p.  197. 

Polycythaemia,  or  erythrocythaemia,  is  a  condition  practically 
the  opposite  to  chlorosis  and  one  due  to  unknown  causes.  As  far  as  is 
known,  pharmacological  agents  exert  no  influence  upon  it,  but  re- 
peated bloodlettings  at  times  give  passing  subjective  and  objective 
relief. 

BIBLIOGRAPHY 
Border:  Med.  Klinik,  1911,  vol.  5,  p.   301,  literature. 

LEUCOCYTES 

Up  to  the  present  time,  there  is  no  satisfactory  explanation  of  the 
manner  in  which  pharmacological  agents  influence  the  leucocytes. 
"While  the  number  of  these  cells  present  in  the  blood  at  the  surface 
of  the  body  may  be  influenced  by  the  distribution  of  the  blood  in 
different  parts  of  the  body  (Bohlandt},  increased  formation  or  an 
increased  emigration  into  the  blood  from  the  organs  in  which  they 
are  formed  may  cause  an  increase  in  their  number.  Thus,  the  leuco- 
cytosis  caused  by  pilocarpine  is  the  result  of  the  contraction  of  the 


LEUCOCYTES  447 

)th  muscles  in  the  spleen  and  the  lymphatic  glands  squeezing 
lymphocytes  into  the  blood,  for  after  ligature  of  the  splenic  vessels 
this  drug  does  not  alter  the  number  of  the  leucocytes  (Harvey)* 
Action  on  the  lymphatic  elements  of  the  intestine  is  the  probable 
cause  of  the  leucocytosis  appearing  during  the  increased  activity  and 
hyperaemia  during  digestion,  as  also  for  that  caused  by  bitters  and 
other  numerous  drugs  which  stimulate  or  irritate  the  alimentary 
mucous  membrane  (Pohl). 

Quinine  and  salicylic  acid  both  possess  a  specific  action  on  the 
leucocytes,  their  movements  being  inhibited  even  by  very  dilute  solu- 
tions, while  concentrated  solutions  kill  them  (Binz). 

The  distribution  of  the  leucocytes  throughout  the  circulation  is 
influenced  by  chemotactic  substances,  and  their  number  may  be 
affected  in  an  indirect-  manner  by  numerous  drugs.  Thus,  the  applica- 
tion of  irritants  to  the  skin  is  followed  at  first  by  hypoleucocytosis, 
later  by  hyperleucocytosis  (Winternitz).  According  to  Hamburger 
and  de  Haan,  lime  salts  specifically  augment  the  motility  and  phago- 
cytic  power  of  the  leucocytes. 

Finally,  the  leucocytes  may  be  destroyed  in  the  circulating  blood,, 
for  they  are  labile  elements  prone  to  destruction  and  succumb  to  the 
action  of  many  destructive  factors  (see  Metabolism).  Thus,  they 
are  destroyed  by  X-rays,  and  in  leukgemia  the  spleen  diminishes  in 
size  (Linser).  [Benzol  has  recently  been  shown  to  greatly  diminish 
the  number  of  leucocytes  in  leukaemia. — TR.] 

On  the  other  hand,  the  destruction  of  the  red  cells  by  specific 
poisons  is  accompanied  by  a  hyperleucocytosis,  due  both  to  increased 
production  of  the  white  cells  and  to  their  being  swept  into  the  blood 
from  the  tissues  (Heinz). 

BIBLIOGRAPHY 
Binz:  Das  Chinin,  Berlin,  1875. 
Bohlandt:   Zbl.  f.  inn.  Med.,  1899. 
de  Haan:   Biochem.  Zeitg.,  1910,  vol.  24,  p.  470. 
Harvey:   Journ.  of  Phys.,  1906,  vol.  35. 

Heinz:,  Handb.  d.  exp.  Path.  u.  Therap.,  1905,  vol.  1,  p.  450. 
Linser  u.  Helber:   D.  Arch.  f.  klin.  Med.,  1905,  vol.  83. 
Pohl:   Arch.  f.  exp.  Path.  u.  Pharm.,   1889,  vol.  25. 
Winternitz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1896,  vol.  36. 

COAGULABILITY 

Among  the  changes  which  take  place  in  the  unformed  elements  of 
the  blood,  its  coagulability  is  one  which  may  be  influenced  by  pharma- 
cological agents, — e.g.,  in  obstinate  bleeding,  purpura  haemorrhagica, 
haemophilia  ( ?). 

According  to  practical  experiences,  the  administration  of  lime  salts 
favors  the  formation  of  firm  clots,*  while  Reverdin  claims  similar  ef- 

*  [Doubt  has  been  thrown  upon  this  claim  by  Cole  and  others  who  have  failed 
to  note  that  such  increase  in  the  coagulability  of  the  blood  followed  the  adminis- 
tration of  lime  in  various  forms  or  that  of  gelatine.  There  is  also  a  difference  of 
opinion  among  clinicians  as  to  this  matter,  which  certainly  needs  further  investi- 
gation.— TR.] 


448  PHARMACOLOGY  OF  THE  BLOOD 

i'ects  from  Glauber 's  salt  by  mouth  or  intravenously,  and  v.  d.  Velden 
claims  the  same  results  for  large  injections  of  NaCl  solutions.  Gelatin 
(15-20  gm.  daily)  internally  or  subcutaneously  is  stated  to  stop  or 
lessen  capillary  bleeding  (A.  Bass).  This  may  be  done  only  to  the 
lime  which  is  present  in  the  gelatin  in  the  amount  of  0.6  per  cent. 
(Zibell).  [It  should  not  be  forgotten  that  cases  of  tetanus  have  been 
caused  by  the  injection  of  insufficiently  sterilized  solutions. — TB.] 

[Epinephrin,  when  injected  intravenously  or  subcutaneously  into 
experimental  animals,  often  causes  an  annoying  increase  in  the  coagu- 
lability of  the  blood.  It  is  possible  that  this  also  occurs  in  man, 
and  it  may  be  that  the  favorable  effects  claimed  from  the  use  of 
this  drug  in  hemorrhage  from  inaccessible  points  is  due  to  such 
action. — TR.] 

THE  DIMINUTION  OR  ABOLITION  OP  THE  COAGULABILITY  of  the  blood 

will  probably  never  be  therapeutically  indicated  unless  to  prevent 
threatening  or  progressive  venous  thrombosis,  but  in  many  ex- 
periments in  animals  such  action  may  be  desirable. 

Sodium  oxalate  or  citrate  (1  to  100),  when  added  to  the  blood,  by  combining 
with  its  calcium  prevents  coagulation.  However,  these  salts  (or  the  depriva- 
tion of  calcium)  are  toxic  for  the  heart  and  the  nervous  system,  and  therefore 
they  cannot  be  used  in  living  animals,  but  only  in  experiments  where  surviving 
organs  are  perfused.  [Here,  too,  their  value  is  very  doubtful. — TB.]  On  the  other 
hand,  the  glands  of  the  leech  contain  a  substance  which  is  harmless  when  in- 
jected and  which  for  a  time  prevents  coagulation  (Haycraft).  Franz  and 
Jacoby  have  named  this  substance  hirudin.  In  the  purest  form  in  which  they 
were  able  to  obtain  it,  it  appeared  to  be  deutero-albumose.  One  milligramme 
of  it  will  permanently  prevent  the  coagulation  of  20  c.c.  of  rabbit's  blood. 

BIBLIOGRAPHY 

Bass,  A.:  Zbl.  f.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1900,  No.  6. 
Franz  u.  Jacoby :  Arch,  f .  exp.  Path.  u.  Pharm.,  1903,  vol.  49. 
Haycraft:  Arch.  f.  exp.  Path.  u.  Pharm.,  1884,  vol.  18. 
Kaposi:  Mitt  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1904,  vol.  13. 
Reverdin:  Rev.  m6d.  de  la  Suisse  rom.,  1895,  p.  506. 
v.  d.  Velden:  Verb.  Kongr.  inn.  Med.,  1909,  p.  155. 
v.  d.  Velden:  Deut.  med.  Woch.,  1909,  No.  5. 
Zibell:  Miinchn.  med.  Woch.,  1901,  No.  42. 

VISCOSITY 

In  recent  years  considerable  attention  has  been  paid  to  the  vis- 
cosity,— i.e.,  to  the  internal  friction — of  the  blood  in  physiological 
and  pathological  conditions  (Kramer),  and  attempts  have  been  made 
to  find  drugs  or  other  agents  which  will  lessen  the  viscosity  and  thus 
facilitate  the  circulation  of  the  blood. 

As  first  claimed  by  Poiseuille  and  confirmed  by  Miiller  and  Inada 
and  by  Kottmann,  potassium  iodide  appears  to  produce  this  effect,  and 
recently  there  is  a  tendency  to  attribute  to  such  action  the  beneficial 
effects  which  follow  the  use  of  this  drug  in  arteriosclerosis.*  The 
diminished  viscosity  resulting  from  the  administration  of  this  drug 
is  not  due  to  any  alteration  of  the  plasma,  but  is  probably  the  result 

*  [See  J.  of  A.  M.  A.,  1912,  for  resum6  of  the  literature— TR.] 


TOXICOLOGY  OF  THE  BLOOD  449 

alteration  of  the  red  cells.  Mere  changes  in  the  volume  of  the  red 
cells  markedly  influence  the  viscosity  of  the  blood,  so  that  the  intro- 
duction of  C02  into  the  blood,  which  augments  the  volume  of  these 
cells,  markedly  increases  the  viscosity.  For  this  reason  in  asphyxia 
the  viscosity  of  the  blood  is  much  increased.  [The  practical  impor- 
tance of  this  effect  of  C02  in  increasing  the  viscosity  of  the  blood  has 
not  been  sufficiently  appreciated  by  the  general  medical  profession. 
In  cases  with  even  moderate  cyanosis,  marked  relief  may  be  given 
to  a  struggling  heart  by  any  measures  which  will  relieve  this  con- 
dition. In  view  of  the  general  skepticism  as  to  the  value  of  oxygen 
inhalations,  these  facts  should  not  be  forgotten. — TR.] 

BIBLIOGRAPHY 

Hirsch  u.  Beck:  Arch.  f.  klin.  Med.,  1901,  vol.  69. 

Kottmann:   Korr.  f.  schweiz.  Aerzte,   1907,  here  literature. 

Kramer:   Bestimmungsmethoden,  Messung  d.  Durchflusszeit  durch  ein    Capillar- 

rohr. 

Muller  u.  Inada:   Deut.  med.  Woch.,  1904. 
Poiseuille:   Ann.  de  chir.  et  de  phys.,   1843. 

ALTERATIONS  IN  THE  CHEMICAL  COMPOSITION  OF  THE  PLASMA. — 
Under  certain  conditions  it  may  be  desirable  to  bring  about  an  altera- 
tion of  the  inorganic  elements  of  the  plasma, — that  is,  to  introduce 
certain  salts  which  appear  to  be  lacking.  In  these  cases,  however,  the 
alteration  or  pathological  composition  is  not  confined  to  the  blood 
alone,  but  affects  all  the  tissue  fluids  and  to  some  degree  the  tissues 
themselves,  including  the  red  cells,  in  so  far  as  the  ions  in  question 
are  able  to  permeate  them.  An  example  of  such  procedure  is  perhaps 
to  be  found  in  the  administration  to  scorbutic  patients  of  the  salts  of 
the  vegetable  acids  and  potassium,  but  this  therapy  rests  on  a  mere 
assumption  for  which  there  is  no  real  scientific  basis.  There  is  no 
doubt,  however,  that  such  is  the  explanation  of  the  benefits  resulting 
from  the  addition  of  NaCl  to  diets  composed  entirely  or  chiefly  of 
vegetable  food,  for  with  such  diet  large  amounts  of  potassium  salts 
through  the  body  and,  by  mass  action,  compel  the  excretion  of  its 
Hum  salts  (Bunge).  (See  Salt  Action,  p.  388.) 

ALKALINITY. — In  conclusion,  mention  should  be  made  of  dimin- 
led  alkalinity  of  the  blood,  a  very  important  condition  and  one 
often  amenable  to  therapeutic  measures.  Evidently  it  is  always 
merely  one  expression  or  symptom  of  a  general  metabolic  disturbance, 
in  which  abnormal  amounts  of  acids  (lactic  acid,  oxy butyric  acid,  and 
others)  accumulate  in  the  body.  (See  Pharm.  of  Metabolism,  p.  389.) 

TOXICOLOGY  OF  THE  BLOOD 

In   addition   to   the  various   therapeutically   useful   agencies   by 
which  the  composition  of  the  blood  may  be  influenced,  there  are  a 
number  of  others  which  are  always  harmful  and  may  thus  be  termed 
blood  poisons.    Of  these  the  more  important  will  be  considered. 
29 


450  PHARMACOLOGY  OF  THE  BLOOD 

CO,  CARBON  MONOXIDE,  the  chief  poisonous  constituent  of  coal-gas 
and  illuminating  gas,  has  an  affinity  for  haemoglobin  about  200  times 
as  strong  as  has  oxygen.  Therefore,  when  present  in  the  atmos- 
phere in  a  concentration  only  1/200  of  that  of  oxygen,  —  i.e.,  in  a  pro- 
portion of  1  to  1000  by  volume,  —  it  is  able  to  replace  one-half  of  the 
oxygen  in  the  hgemoglobin,  and  in  higher  concentrations  to  replace 
it  almost  entirely. 

By  use  of  the  following  equation,  it  is  possible  to  calculate  the  extent  to 
which  a  given  amount  of  CO  will  replace  the  oxygen  in  blood  at  body  tem- 
perature (Hufner), 

__  100 

"  0.006518  '  -|^  +  1 

If  Vo  =  percentage  of  02  in  the  air  and  Vc  =  percentage  of  CO,  then  a?  =  the 
percentage  of  the  haemoglobin  which  will  combine  with   CO. 

If,  for  example,  the  air  contains  21  per  cent.  O2  and  0.1  per  cent.  CO, 

100  100 

-    —  21  -    =   OQROQ   =  42-21  Percent. 


0.006518---+  1 

i.e.,  under  these  conditions  nearly  one-half  of  the  blood  would  be  saturated  with 
CO  if  the  subject  remained  in  such  an  atmosphere  sufficiently  long. 

If  the  air  contain  0.3  per  cent.  CO,  x  =  68.7  per  cent.,  and  human 
beings  cannot  survive  such  conditions,  for  in  them  death  results  when 
60-70  per  cent,  of  their  haemoglobin  is  saturated  with  CO.  In  birds, 
with  their  higher  temperature,  50-60  per  cent.  CO  saturation  of  the 
blood  is  fatal,  but  rabbits  survive  up  to  nearly  80-90  per  cent.  (Dreser, 
Hufner).  If  the  supply  of  CO  ceases  (before  death  ensues),  or,  other- 
wise expressed,  if  its  concentration  in  the  air  sinks  to  zero,  it  is 
gradually  driven  out  from  the  blood  by  the  pure  air  breathed  in,  and 
the  larger  the  amounts  of  oxygen  in  the  air  the  more  rapidly  does 
this  occur.  The  recovery  from  poisoning  by  carbon  monoxide  is,  there- 
fore, materially  accelerated  when  pure  oxygen  is  inhaled.  [Direct 
arm-to-arm  transfusion  of  blood  is  also  doubtless  a  life-saving  pro- 
cedure in  ,such  eases,  and  in  extremely  grave  cases  should,  when 
feasible,  be  employed.  —  TR.] 

BIBLIOGRAPHY 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  29. 
Hufner:  Journ.  f.  prakt.  Chem.,  1884,  vol.  30,  p.  68. 
Hufner:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48. 

HYDROCYANIC  ACID.  —  In  poisoning  by  this  acid,  which  kills  by 
rapid  paralysis  of  the  respiratory  centre,  the  blood  also  is  affected, 
the  absorption  of  oxygen  by  the  oxidizable  elements  of  the  body  cells 
being  interfered  with  or  prevented,  just  as  other  so-called  catalytic 
processes  are  inhibited  by  HCN  (Gaehtgens,  Geppert).  For  this 
reason,  the  venous  blood  has  almost  the  same  color  and  02 
content  as  arterial  blood.  Methaemoglobin  resulting  from  decompo- 


TOXICOLOGY  OF  THE  BLOOD  451 

sition  or  other  processes  forms  with  cyanides  a  bright  red  combination, 
cyanhaemoglobin,  which  at  times  renders  possible  the  recognition  of 
cyanides  as  the  cause  of  death  (Robert,  v.  Zeynek). 

BIBLIOGRAPHY 

Gaehtgens:  Med.-chem.  Untersuch.,  Berlin,  1868,  No.  3. 
Geppert:   Ztschr.  f.  klin.  Med.,  1889,  vol.  15. 
Kobert:   Ueber  Cyanmethiimoglobin,  1881. 
v.  Zeynek:  Ztschr.  f.  physiol.  Chem.,  1901,  vol.  33. 

METH^MOGLOBIN  is  formed  from  oxyhcemoglobin  by  the  action 
of  a  large  number  of  substances.  This  is  a  combination  of  oxygen  and 
haemoglobin,  in  which  the  oxygen  is  so  firmly  combined  that  it  is  not 
available  for  the  internal  respiration  of  the  tissues.  Such  blood  is 
of  a  reddish-brown  or  in  extreme  cases  of  a  coffee  color.  By  reducing 
agents,  methaemoglobin  is  changed  to  normal  haemoglobin,  and  in  this 
way  the  reducing  substances  present  in  normal  blood  may  transform 
small  amounts  of  methaemoglobin  to  haemoglobin,  otherwise  cells  thus 
affected  disintegrate  and  the  coloring  matter  dissolves  in  the  blood, 
which  may  cause  serious  results,  such  as  methaemoglobinuria,  blocking 
of  the  uriniferous  tubules,  and  urasmia. 

Of  the  substances  which  thus  affect  the  red  cells  the  most  im- 
portant are  the  chlorates,  nitrites,  and  aniline  and  some  of  its  deriva- 
tives, especially  acetanilide.  [Many  of  the  salicylates  and  other  anti- 
pyretics produce  analogous  changes  in  the  blood  to  a  less  degree,  but 
still  to  an  extent  which  may  under  certain  conditions  prove  of  prac- 
tical significance  (see  p.  478).  The  sulphones,  sulphonal,  trional,  and 
tetronal  form  from  haemoglobin  a  pigment,  hsematoporphyrin,  which  is 
excreted  in  the  urine.  Pyrogallol,  much  used  in  photography,  should 
also  be  mentioned  in  this  connection. — TR.] 

HAEMOLYSIS 

Hagmolysis,^-i.e.,  a  dissolving  of  the  red  cells  of  the  plasma — 
occurs  if  the  osmotic  tension  of  the  blood  sinks  appreciably  below  that 
of  these  cells.  This  occurs,  for  example,  if  the  blood  be  markedly 
diluted  by  the  infusion  of  pure  water.  If  under  special  conditions 
the  osmotic  tension  of  the  corpuscles  has  been  markedly  increased 
over  that  of  the  plasma,  this,  too,  results  in  haemolysis.  Such  may  be 
the  case  if  the  blood  has  been  strongly  concentrated  in  some  portion 
of  the  body  by  the  injection  into  the  tissues  of  substances  which 
strongly  attract  water, — e.g.,  concentrated  salt  solutions  or  glycerin. 
(This  occurs  especially  if  stasis  exists.)  If  then  the  distended 
hypertonic  red  cells  pass  with  the  blood  into  other  portions  of  the 
body  where  the  plasma  is  of  normal  tension,  they  undergo  haemolysis 
(Filehne). 

A  hasmolytic  action  is  also  produced  by  all  substances  which 
chemically  or  physicochemically  attack  any  integral  components  of  the 


452  PHARMACOLOGY  OF  THE  BLOOD 

corpuscular  stroma  and  thus  destroy  the  balance  of  the  normal  pro- 
toplasmic combinations.  Saponin,  on  account  of  its  strong  affinity  to 
cholesterin,  exerts  this  action  (Ransom),  as  do  ether,  chloroform,  and 
all  the  narcotics  of  this  group,  by  virtue  of  their  affinity  to  the 
lecithin  present  in  the  red  cells.  From  a  practical  stand-point  these 
toxic  actions  are  of  no  moment,  for  saponin  cannot  pass  unchanged 
through  the  mucous  membrane  of  the  alimentary  tract  and  the  nar- 
cotics do  not  attain  a  sufficient  concentration  in  the  blood.  [Repeated 
administrations  of  chloroform,  and  probably  also  of  ether,  do  cause 
a  distinct  anaBmia,  probably  due  to  this  cause,  and  in  the  rabbit  such 
haemolysis  due  to  ether  is  frequently  observed. — TR.]  The  haemolysin 
contained  in  Morchella  esculenta  (Bohm),  an  edible  mushroom,  which 
is  readily  absorbed  from  the  stomach  into  the  blood,  is  practically 
important.  It  is  removed  from  the  fresh  mushrooms  by  boiling  with 
water  and  appears  to  be  destroyed  by  drying.  It  is  not  known  which 
component  of  the  corpuscles  it  combines  with.  The  same  is  true  of 
AsH3,  which  haemolyzes  the  blood-cells  when  inhaled  in  even  very 
small  quantities. 

Finally,  the  Jucmolytic  toxins,  such  as  those  in  snake  venoms, — e.g., 
in  cobra  venom  [and  haemolysins  formed  by  bacterial  action. — TR.], — 
should  be  mentioned,  as  also  haemolysis  by  heterogeneous  sera. 

The  effects  of  haemolysis  are  very  varied.  In  case  of  very  extensive 
and  rapid  dissolution  of  the  blood,  the  setting  free  of  fibrin-ferment 
may  cause  clotting  in  the  vessels,  with  fatal  results.  With  less  marked 
haemolysis  the  abnormal  amount  of  dissolved  haamoglobin  causes  an 
abnormally  large  production  of  bile-pigments  and  jaundice,  while  that 
portion  of  the  haemoglobin  which  is  not  retained  by  the  liver  and 
spleen  is  excreted  by  the  kidneys,  where  it  may  block  the  uriniferous 
tubules  and  cause  anuria. 

In  haemolysis  not  only  the  coloring  matter  of  the  blood-cells 
but  also  their  lipoids  (lecithin,  etc.)  and  salts  enter  the  plasma.  If, 
as  is  the  case  in  many  species,  the  erythrocytes  contain  large  amounts 
of  potassium  salts,  these  may  fatally  poison  the  heart.  The  liberated 
lipoids,  if  derived  from  the  cells  of  the  same  species,  are  relatively 
harmless,  but  the  heterogeneous  ones  are  extraordinarily  poisonous. 
Rabbit's  blood  injected  intravenously  into  a  dog  is  haemolyzed  by  the 
dog's  plasma,  and  the  liberated  lipoids  quickly  paralyze  the  respiration 
and  the  central  nervous  system  (Gottlieb  u.  Lefmann).  It  is  these 
poisonous  components  of  the  dissolved  red  cells  which  are  responsible 
for  the  dangerous  effects  of  the  transfusion  of  heterogeneous  blood, 
which,  when  haemolyzed,  at  once  becomes  very  poisonous. 

BIBLIOGRAPHY 

Bohm  u.  Kiilz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1882,  vol.  19,  p.  445. 

Filehne:  Virchow's  Arch.,  1889,  vol.  117,  p.  413. 

Gottlieb  u.  Lefmann:  Med.  Klinik,  1907. 

Lefmann:  Hofmeister's  Beitr.  z.  chem.  Physiol.,  1908,  vol.  11,  p.  255. 

Ransom:  Deut.  med.  Woch.,   1901,  No.   13. 


CHAPTER  XV 


ANTIPYRETICS 

ALL  the  drugs  which  exert  an  influence  on  the  temperature  act 
much  more  strongly  on  febrile  than  on  normal  temperature.  How- 
ever, fundamental  differences  in  their  action  on  the  normal  and  on  the 
diseased  organism  exist  only  in  those  antipyretics  which,  like  quinine 
in  malaria,  exert  a  direct  influence  on  the  cause  of  the  fever  (see 
Etiotropic  Agents,  p.  527),  while  the  great  majority  of  the  drugs 
of  this  group  exert  their  influence  only  on  the  symptom  of  increased 
temperature.  That  even  these  purely  symptomatically  active  antipy- 
retics lower  the  temperature  of  febrile  individuals  so  much  more 
markedly  than  they  do  that  of  the  healthy  is  due  to  the  different 
behavior  of  the  heat-regulating  mechanism  in  health  and  in  fever. 

THE  HEAT-REGULATING  MECHANISM 

The  heat-regulating  mechanism  includes  all  those  processes  taken 
as  a  whole  by  which  the  body  temperature  is  maintained  constant  in 
spite  of  the  changing  temperature  of  its  environment.  In  the  cold- 
blooded animals,  in  which  there  is  no  heat  regulation,  the  production 
of  heat  and  the  body  temperature  rise  and  fall  with  the  external 
temperature,  but  in  the  warm-blooded  animals  heat  and  cold  are 
effective  stimuli  for  a  number  of  physiological  processes,  whose  pro- 
tecting influence  enables  the  organism  to  maintain  its  own  proper 
temperature  in  spite  of  a  lowering  or  raising  of  the  external  tem- 
perature. These  processes  are  in  part  local  ones,  which  occur  in  the 
cooled  or  warmed  surface  of  the  body,  and  in  part  are  the  results  of 
complicated  remote  actions  induced  reflexly. 

By  the  local  action  of  cold,  the  cutaneous  vessels  are  constricted 
in  those  regions  of  the  skin  which  are  affected,  and  the  skin  becomes 
anaemic,  pale,  and  cold  (F.  Frank,  Mosso),  and,  as  the  skin  with  its 
cushion  of  subcutaneous  fat  is  a  poor  conductor  of  heat,  it  acts  as  a 
protecting  cover  to  the  internal  organs.  On  the  other  hand,  heat  causes 
local  relaxation  of  the  cutaneous  vessels  and  consequently  redness 
and  a  freer  flow  of  blood  to  the  skin.  Here  these  effects  are  at  least 
in  part  due  to  a  direct  action  of  cold  and  heat  on  the  vessel  walls, 
for  even  the  vessels  of  a  surviving  organ  which  has  been  isolated  from 
the  central  nervous  system  dilate  under  the  influence  of  heat  and 
contract  under  that  of  cold  (Lewaschew,  Bernstein,  Langendorff). 

Cold,  however,  acts  not  only  on  the  vessels  of  that  portion  of  the 

453 


454  PHARMACOLOGY  OF  HEAT  REGULATION 

skin  which  is  directly  exposed  to  it,  but  also  on  its  temperature  nerves, 
and,  as  a  result,  there  is  a  subjective  feeling  of  cold,  for  only  when 
the  skin  is  poorly  supplied  with  blood  and  is  itself  cool  do  we  feel 
cold.  Cold  also  excites  reflexes  which  limit  the  loss  of  heat  by  the 
body  and  increase  its  production. 

This  limitation  of  the  heat  output  is  brought  about  by  a  reflexly 
induced  constriction  of  all  the  cutaneous  vessels,  not  only  in  the 
parts  directly  exposed  to  the  cold  but  also  over  the  whole  surface 
of  the  body,  which  becomes  pale  and  anaemic,  and  consequently  a 
general  feeling  of  cold  may  be  produced  by  the  cooling  of  only  one 
part  of  the  body.  Such  reflexes  may  be  especially  well  demonstrated 
by  plunging  one  hand  into  very  cold  water,  in  which  case  the  tem- 
perature of  the  skin  of  the  other  hand  is  found  to  be  diminished 
(Brown-Sequard  et  Tholozan).  Slight  cooling  of  one  arm  also  causes 
a  distinct  diminution  in  the  volume  of  the  other,  as  may  be  shown 
plethysmographically  (Amitin,  Lommel}.  Similarly  cold  applied 
locally,  by  diminishing  the  blood  content  of  the  superficial  portion  of 
the  body,  especially  in  the  skin  and'  -muscles,  may  cause  a  very  pro- 
nounced alteration  in  the  distribution  of  the  blood,  so  that  the  ab- 
dominal organs  receive  a  greatly  increased  blood  supply  (0.  Muller}. 

This  constriction  of  the  cutaneous  vessels  resulting  from  the  stimu- 
lus of  cold  protects  the  organism  in  a  double  fashion.  First,  a  smaller 
portion  of  the  total  quantity  of  the  blood  is  exposed  to  cooling  in 
the  skin,  and  consequently  the  blood  returns  to  the  heart  at  a  less 
diminished  temperature ;  and,  secondly,  more  blood  is  diverted  to  the 
internal  organs,  in  which  its  temperature  is  raised.  As  a  result  of 
this  alteration  in  the  distribution  of  the  blood,  the  loss  of  heat  caused 
by  a  lowered  external  temperature  is  limited,  and.  the  blood  tempera- 
ture remains  constant  so  long  as  this  physical  heat  regulation  is  suffi- 
cient to  accomplish  this  end.  When,  however,  it  alone  is  no  longer 
sufficient,  as,  for  example,  when  one  remains  for  a  considerable  time 
in  a  cold  bath,  a  second  regulatory  mechanism  is  called  reflexly  into 
play, — the  chemical  heat  regulation  (Eubner}. 

In  the  latter  case  the  organism  protects  itself  by  increased  com- 
bustion, as  shown  by  the  fact  that,  when  this  chemical  regulatory 
mechanism  is  called  into  play,  the  carbon  dioxide  output  rises  with  the 
greatest  regularity  as  the  external  temperature  is  gradually  decreased 
(Wolpert}.  This  reflexly  augmented  production  of  heat  occurs 
chiefly  in  the  muscles,  and  at  the  start  without  the  occurrence  of  any 
visible  movements,  the  increase  in  the  production  of  heat  being 
unaccompanied  by  any  performance  of  mechanical  muscular  work. 
Besides  the  muscles,  the  great  glands  of  the  body  also  play  a  role 
in  the  production  of  heat,  so  that  the  reflexes  resulting  from  external 
cold  affect  the  functions  of  practically  all  the  organs  of  the  body. 

Pharmacologically  it  is  of  some  significance  that  the  subjective 
feeling  of  cold  and  the  protective  processes  which  are  excited  by 


PHYSIOLOGY  455 

stimulation  of  temperature  nerves  are  dependent  on  the  character 
and  extent  of  the  blood  flow  through  the  skin,  for,  if  the  cooling  off 
of  the  skin  is  prevented  by  paralyzing  the  cutaneous  vessels, — e.g., 
by  alcohol, — so  that  these,  in  spite  of  the  low  temperature,  continue  to 
receive  large  amounts  of  blood,  the  internal  temperature  of  the  body 
falls,  but  the  individual  does  not  feel  cold  because  the  temperature  of 
the  skin  has  not  been  lowered.  Under  these  conditions,  however,  the 
stimulus,  which  causes  the  normal  voluntary  and  involuntary  protec- 
tive reactions,  which  originate  in  the  skin,  is  lacking,  and,  as  a  con- 
sequence, the  body  continues  to  lose  more  and  more  heat.  This 
is  the  explanation  of  the  danger  of  freezing  to  death  which  is  caused 
by  all  narcotic  poisons  which  paralyze  the  vessels'  of  the  skin,  a  danger 
which  is  especially  great  in  alcoholic  intoxication. 

Like  the  regulation  of  the  body  temperature  against  cooling,  the 
protection  against  overheating  is  also  controlled  by  the  nervous  sys- 
tem, the  cutaneous  vessels  being  dilated,  the  secretion  of  sweat  excited, 
and  the  respiration  accelerated,  so  that  more  heat  is  given  off  through 
the  skin  and  the  lungs,  all  these  effects  being  brought  about  by  the 
activity  of  various  nervous  centres.  The  dilatation  of  the  cutaneous 
vessels  causes  a  larger  quantity  of  blood  to  be  exposed  to  the  external 
cold,  and  the  evaporation  of  the  sweat  from  the  surface  of  the  skin 
absorbs  a  large  amount  of  heat  which  is  thus  removed  from  the  body. 
On  the  other  hand,  animals  which  are  not  able  to  sweat  and  which 
possess  a  thick  hairy  coat  get  rid  of  their  superfluous  heat  chiefly 
by  rapid  breathing  and  the  evaporation  of  water  which  results  there- 
from. 

The  dog,  for  example,  is  able  to  augment  the  heat  loss  from  the  skin  only 
very  slightly,  and  consequently  he  accomplishes  his  heat  regulation  by  means  of 
very  rapid  breathing,  blowing  the  air  over  the  widely  protruded  tongue,  whose 
broad  surface  is  kept  constantly  moistened  with  saliva  and  mucus  and  offers 
an  exceptional  opportunity  for  the  evaporation  of  water.  If  dogs  be  forced 
to  work  and  this  very  important  regulatory  mechanism  be  interfered  with  by 
previous  tracheotomy,  death  ensues  as  a  result  of  overheating  (Zuntz), 

In  man,  besides  dilatation  of  the  cutaneous  vessels,  the  secretion 
of  sweat  is  the  most  efficient  means  of  removing  large  quantities  of 
heat  from  the  body,  for  the  evaporation  of  1  c.c.  of  water  requires 
as  much  as  0.54  calorie,  and  consequently  the  excess  of  heat  may  be 
lost  simply  by  the  aid  of  the  physical  heat  regulation,  even  during 
the  performance  of  large  amounts  of  mechanical  work,  as  in  marching 
(Zuntz},  and,  therefore,  there  is  no  need  of  a  chemically  regulated 
limitation  of  the  production  of  heat  to  protect  the  organism  from 
overheating. 

Such  regulation  against  overheating  can  also  be  directly  called  into 
play  by  a  very  slight  increase  in  the  temperature  of  the  blood,  for, 
without  altering  the  temperature  of  the  blood  in  the  rest  of  the  body, 
all  the  signs  of  the  physical  regulation  against  overheating  may  be 


456  PHARMACOLOGY  OF  HEAT  REGULATION 

caused  to  appear  by  simply  warming  the  blood  in  the  carotid  on  its 
way  to  the  brain,  this  alone  being  sufficient  to  cause  dilatation  of 
the  cutaneous  vessels,  increased  secretion  of  sweat,  and  heat  dyspnoea 
(Kahri). 

It  is  thus  apparent  that  the  heat-regulating  centres  can  be  stimu- 
lated to  their  reaction  against  a  low  external  temperature  not  only 
reflexly  but  also  by  a  diminution,  even  though  a  minimal  one,  of  the 
temperature  of  the  blood  (Stern,  Strasser),  while  in  their  reaction 
against  overheating  they  are  influenced  both  by  the  temperature  of 
the  blood  and  also  reflexly  from  the  skin,  for  such  signs  of  com- 
pensatory regulation  as  sweating  can  appear  under  the  influence  of 
heat  stimuli  even  before  any  augmentation  of  the  temperature  of  the 
body  has  occurred  (Stern,  Strasser,  Filehne).  "While  this  is  true, 
still  under  all  conditions  it  is  the  central  nervous  system  which 
keeps  the  body  temperature  constant. 

From  what  has  already  been  said,  it  is  evident  that  the  physi- 
ological regulation  of  heat  is  accomplished  by  a  very  complicated 
mechanism,  in  which  the  vasomotor  and  secretory  centres  are  in- 
fluenced by  a  higher  centre  or  centres.  The  organs  in  which  the 
loss  of  heat  occurs  are  connected  nervously  through  such  heat-regulat- 
ing centres  with  the  organs — the  muscles  and  the  glands — in  which 
the  heat  is  produced.  Up  to  the  present,  however,  our  knowledge  of 
the  details  of  this  relationship  between  these  various  regulatory  pro- 
cesses is  very  incomplete.  Certain  it  is  only  that  the  temperature 
equilibrium  is  maintained  by  this  mechanism  in  such  fashion  that  the 
production  and  output  of  heat  always  keep  pace  with  each  other  so 
long  as  the  heat-regulatory  mechanism  in  the  central  nervous  system 
continues  to  function  normally.  Under  all  the  changing  conditions 
of  external  temperature,  as  also  in  spite  of  all  variations  in  the  com- 
bustive  processes  in  the  organism,  the  body  temperature  remains 
constant,  because,  with  every  change  in  the  metabolism, — as,  for  ex- 
ample, when  food  is  ingested  or  when  muscular  work  is  performed, — 
the  output  of  heat  simultaneously  changes  in  a  corresponding  direc- 
tion, and  because,  if  this  physical  regulation  does  not  suffice,  the  pro- 
duction of  heat  is  also  regulated  so  as  to  correspond  to  the  changing 
demands  occasioned  by  the  loss  of  heat.  In  this  fashion  the  equilib- 
rium of  the  heat  economy  of  the  body  can  be  maintained,  even 
in  spite  of  very  great  variations  in  the  amount  of  heat  produced  or 
lost.  The  maintenance  of  the  normal  body  temperature  depends  simply 
on  any  alteration  of  one  factor  being  compensated  by  a  regulatory 
alteration  of  the  other,  so  that  the  momentary  heat  loss  may  always 
equal  the  momentary  heat  production,  the  amount  of  heat  in  the  body 
being  thus  kept  constant. 

These  relationships  may  be  expressed  by  a  diagram  (see  Fig.  55), 
in  which  the  changing  values  of  heat  production  and  output  are  shown 


PHYSIOLOGY 


457 


as  ordinates.  Under  normal  conditions  they  coincide  with  each  other, 
and  there  is  no  interval  between  them  so  long  as  the  body  temperature 
remains  normal. 

The  curve  below  represents  the  body  temperature  under  different 
conditions.  It  remains  normal  if  under  normal  conditions  the  pro- 
duction and  output  of  heat  are  equal,  also  when  both  are  equally  in- 
creased, as,  for  example,  during  muscular  work.  In  long-continued 
hunger  the  body  temperature  falls  as  a  result  of  the  diminution  of  the 
production  of  heat.  In  fever  it  rises,  because  of  the  lagging  behind 
of  the  heat  output  and  because  of  the  increase  in  the  heat  production 
which  then  follows.  In  the  crisis  it  falls,  because  the  heat  production 
lags  behind  the  heat  output. 


-39" 


Temperature 


\ 


v.---' 


Normal 


Work  Rest,  fasting     Normal 

.Heat  production 
•  Heat  loss 


Chill 


Fastigium  Crisis  | 
Sweating 


Normal 


Subnormal 


FIG.  55. 


Such  a  coordinated  cooperation  between  heat  production  and  heat 
loss  could  be  obtained  only  by  a  centrally  connected  control  of  both 
processes,  for  the  controlling  heat  centres  must  necessarily  be  able 
both  to  influence  the  organs  through  which  heat  is  lost  and  to  control 
the  metabolism  in  the  tissues. 

The  reaction  of  these  heat  centres  to  cooling  may  be  interpreted 
as  consisting  in  an  augmented  state  of  excitation  of  the  regulating 
centres.  Even  under  normal  conditions  stimuli  are  carried  through 
the  sensory  centres  of  the  skin  to  the  centres  for  the  constriction  of 
the  cutaneous  vessels,  and,  if  the  temperature  of  the  skin  falls,  this 
reflex  stimulation  becomes  stronger,  and  consequently  the  heat  out- 
put is  diminished.  The  chemical  heat  regulation, — that  is,  the  aug- 
mentation of  the  processes  by  which  heat  is  produced, — which  is 
excited  by  cooling  of  the  body,  also  depends  upon  an  augmentation  of 
the  nervous  impulses  which  accelerate  the  chemical  processes  in  the 
muscles,  which  can  even  be  so  augmented  as  to  cause  visible  muscular 
movements,  such  as  shivering  when  one  is  chilled.  That  this  conser- 
vation and  production  of  heat  is  due  to  an  augmented  excita- 
tion of  the  centres  is  indicated,  above  all,  by  the  fact  that  the  same 
effects,  diminution  of  the  output  and  augmentation  of  the  production 
of  heat,  may  also  be  produced  by  direct  mechanical  or  electrical  stimu- 


458  PHARMACOLOGY  OF  HEAT  REGULATION 

lation  of  certain  regions  of  the  brain  (Aronsohn  u.  Sachs,  Richet, 
Ott}.  In  the  rabbit,  dog,  and  horse  such  a  point  lies  in  the  head  of  the 
corpus  striatum. 

The  reaction  of  the  organism  against  overheating  can,  on  the  other 
hand,  be  assumed  to  be  due  to  a  depression  of  the  excitability  in  the 
same  centres,  these  centres,  under  the  influence  of  overheated  blood, 
moderating  the  impulses  which  they  send  to  the  vasomotor  centres. 
In  accordance  with  this  is  the  observation  of  Kahn  that  overheat- 
ing of  the  carotid  blood  acts  as  a  sedative  on  other  centres  also, 
the  animals  being,  as  it  were,  narcotized.  These  assumptions  are  in 
no  way  inconsistent  with  the  fact  that,  associated  with  this  sedative 
action  on  these  regulatory  controlling  centres,  there  is  an  augmented 
activity  of  the  subsidiary  centres,  which  causes  secretion  of  sweat, 
heat  dyspnoea,  etc.,  for  often  enough  in  physiology  one  meets  with 
examples  of  such  opposing  actions  on  controlling  and  subsidiary 
centres. 

It  will  be  shown  later  that  the  actions  of  pyrogenous  poisons  and  of 
antipyretics  are  quite  consistent  with  this  assumption  that  conserva- 
tion of  heat  is  due  to  a  stimulation  of  the  heat-regulating  centres,  and 
that  increased  output  of  heat  is  due  to  sedative  action  on  them. 

Although  we  speak  of  heat-regulating  centres,  it  is  by  no  means  implied 
that  these  have  been  anatomically  located,  for  anatomically  we  know  of  no 
heat  centre.  The  structures  affected  by  the  heat  puncture  may  be  centres  or 
— and  quite  as  probably — simply  nervous  tracts  which  are  connected  with 
various  scattered  centres.  However,  we  are  forced  to  assume  in  a  physiological 
sense  a  heat-regulating  centre,  meaning  by  this  term  a  controlling  central 
mechanism,  which  secures  a  coordinated  cooperation  of  vasomotor  and  sweat 
centres,  and  which  also  furnishes  the  necessary  nervous  impulses  to  control  the 
metabolism,  so  that  the  equilibrium  of  the  temperature  may  be  maintained. 
These  centres  certainly  do  not  lie  lower  than  the  midbrain,  for,  after  destruc- 
tion of  this  or  after  high  division  of  the  cord,  warm-blooded  animals  behave 
like  cold-blooded  animals,  their  body  temperature  becoming  dependent  on  the 
temperature  of  the  environment. 

BIBLIOGRAPHY 

Amitin,  S. :   Ztschr.  f.  Biol.,  1897,  vol.  35,  p.  13. 

Aronsohn  u.  Sachs:   Pflilger's  Arch.,  1885,  vol.  37,  p.  232. 

Bernstein:   Lehrb.  d.  Physiol.,  Stuttgart,  1894,  p.  110. 

Brown-Sequard  et  Tholozan,  cited  by  Morat  et  Doyon:  Traite  de  Physiol.,  1899, 

vol.  3,  p.  490. 

Filehne,  O.:  Arch.  f.  Physiol.,  1910,  p.  501. 
Franck,  Frangois:  Traveaux  du  Laboratoire  de  Marey,  1876. 
Kahn,  R.  H.:  Engelmann's  Arch.  f.  Physiol.,  1904,  Suppl.,  p.  90. 
Langendorff:   Pfluger's  Arch.,  1897,  vol.  66,  p.  387. 
Lewaschew:   Pfliiger'a  Arch.,  1881,  vol.  26,  p.  60. 
Lommel:  Deut.  Arch.  f.  klin.  Med.,  1904. 
Mosso:  Archives  italiennea  de  Biologic,  1889. 
Miiller,  0.:   Habilitationsschrift,  Tubingen,   1905. 
Ott:  Journ.  of  Nervous  and  Mental  Diseases,  1884. 
Richet:   Compt.  rend.,  1884  and  1885. 
Rubner:  Biologische  Gesetze,  Marburg,  1887. 
Stern,  R. :  Ztschr.  f .  klin.  Med.,  vol.  20,  p.  63. 
Strasser:  Med.  Klinik,  1910,  No.  28. 
Wolpert:   Arch.  f.  Hygiene,  1898,  vol.  33,  p.  206. 
Zuntz:   Vortr.  Balneolog.  Gesellsch.,  March  6,  1903. 


MECHANISM  OF  FEVER  459 

FEVER 

In  infectious  diseases  pyrogenous  substances,  by  their  action  on 
the  heat-regulating  centres,  cause  a  rise  in  the  body  temperature 
(Krehl),  for  bacterial  toxins  cause  a  toxicogenic  decomposition  of 
proteids,  and  the  peculiar  products  of  this  pathological  decomposition 
of  protoplasm  or  the  bacterial  toxins  themselves  disturb  the  normal 
processes  of  heat  regulation. 

Various  investigations  of  the  production  and  conservation  of  heat 
in  febrile  men  and  animals  (Krehl  u.  Matthes)  have  shown  that,  as 
a  rule,  while  the  heat  production  is  distinctly  augmented,  this  aug- 
mentation is  not  very  great,  amounting  to  only  about  20-30  per  cent, 
increase  above  the  normal  value  (Krehl}.  Inasmuch  as  in  the  organ- 
ism, so  long  as  the  heat  regulation  is  functioning  normally,  the  pro- 
duction of  heat  may  be  increased  as  much  as  60  per  cent,  by  the  free 
ingestion  of  food,  and  by  muscular  work  even  more,  without  the  tem- 
perature rising,  it  is  evident  that  a  30  per  cent,  increase  in  heat 
production  cannot  by  itself  be  the  cause  of  the  augmentation  of  the 
temperature,  and  consequently  in  fever  there  must  also  be  some  other 
disturbance  of  the  temperature  regulation.  This  is  in  fact  the 
case,  for,  while  normally  an  increase  in  heat  production  is  readily 
compensated  for  by  increased  heat  output,  this  latter  is  either  ab- 
solutely diminished  in  fever  or  is  less  increased  than  is  the  heat  pro- 
duction. 

Calorimetric  determination  of  the  total  heat  output  of  febrile  animals 
(Krehl  u.  Matthes)  shows  that  this  is  diminished  during  the  period  in  which 
the  fever  is  rising,  and  in  man  the  coldness  and  pallor  of  the  skin  during  the 
chill,  by  themselves,  show  that  the  cutaneous  vessels  are  contracted.  This  has 
been  definitely  proven  by  Haragliano's  plethysmographic  studies  and  by  Oeigel's 
and  Kraus's  thermo-electric  investigations.  Furthermore,  C.  Rosenthal's  partial 
calometric  observations  have  demonstrated  the  diminution  of  the  heat  loss  by 
conduction  and  radiation. 

It  is  thus  evident  that  in  fever  the  temperature  rises  as  a  result 
of  limitation  of  the  heat  output  while  at  the  same  time  the  heat 
production  is,  as  a  rule,  augmented.  In  fever  the  organism  behaves 
as  if  it  were  necessary  to  conserve  ^ts  heat,  combusting  more  material 
than  ordinarily  and  parting  with  as  little  of  its  heat  as  is  possible. 

One  might  be  tempted  to  conclude  that  in  fever  the  heat  centres 
had  entirely  lost  control  of  the  peripheral  mechanism  by  which  heat 
is  lost  and  produced,  and  that  consequently  they  are  no  longer  able 
to  maintain  a  balance  between  these  two  functions.  This,  however, 
is  not  at  all  the  case,  for,  as  shown  by  Liebermeister  and  Stern  in  man, 
and  by  numerous  others  (Colasanti,  Finkler,  Lilienfeld,  etc.)  in 
febrile  animals,  the  febrile  organism  reacts  to  cooling  influences  by 
augmentation  of  heat  production  and  to  artificial  overheating  by 
increasing  its  heat  output.  However,  the  heat  regulation  is  no  longer 
so  efficient  or  complete  as  in  normal  conditions,  and  consequently  the 


460  PHARMACOLOGY  OF  HEAT  REGULATION 

febrile  temperature  is  more  readily  altered  by  external  influences 
than  is  the  normal  temperature. 

From  the  above  it  is  evident  that  in  fever  the  body  has  by  no 
means  lost  its  power  of  heat  regulation,  but,  as  production  and  loss  of 
heat  are  no  longer  so  controlled  that  the  normal  temperature  is  main- 
tained and  as,  on  the  contrary,  the  febrile  organism  regulates  these 
processes  in  such  a  fashion  that  it  maintains  its  abnormal  tempera- 
ture, we  are  compelled  to  conclude  that  in  fever  the  heat-regulating 
centres  function  in  an  abnormal  fashion.  As  long  ago  as  1875,  such 
observations  led  Liebermeister  to  formulate  the  hypothesis  that  in 
fever  the  heat  regulation  is  "  set  "  for  a  higher  temperature.  As 
a  matter  of  fact,  at  the  height  of  any  fever  a  regulatory  augmentation 
of  the  heat  output  occurs,  for  otherwise  the  temperature  of  the  body 
would  rise  constantly  higher  and  higher  because  of  the  constantly 
increasing  augmentation  of  heat  production.  However,  so  long  as  the 
pathological  condition  of  the  heat  centres  persists,  the  heat  loss  is 
augmented  only  enough  to  maintain  the  temperature  at  a  febrile 
height,  but  not  enough  to  bring  it  back  to  normal. 

To-day  it  is  possible  to  form  a  more  precise  conception  of  the 
manner  in  which  in  fever  the  heat  mechanism  is  ' '  set  ' '  for  an  abnor- 
mal temperature,  and  of  the  manner  in  which  this  is  corrected  by  an- 
tipyretics (Filehne).  An  analogy  between  infectious  fever  and  punc- 
ture hyperthermia  has  been  of  much  assistance  here,  for  it  has  been 
found  that  heat  regulation  in  both  of  these  types  of  fever  is  essentially 
similar.  In  the  fever  resulting  from  the  mechanical  irritation  of  the 
corpus  striatum  there  is  an  augmentation  of  the  heat  production 
(Schultze),  while  during  the  period  of  rising  temperature  the  heat 
output  is  absolutely  diminished  or  at  least  relatively  insufficient 
(Gottlieb,  Eichter,  Schultze),  just  as  in  infectious  fever.  In  it,  too, 
the  power  of  regulating  the  temperature  is  retained  and  comes  into 
action  when  the  external  temperature  changes  (Schultze}.  At  the 
height  of  the  fever  thus  produced,  the  heat  output  is  augmented,  just 
as  in  infectious  fever,  but  only  enough  to  enable  the  organism  to 
maintain  its  febrile  temperature.  It  is  thus  seen  that  there  is  a  wide- 
reaching  analogy  between  puncture  hyperthermia  and  infectious  fever. 

Although  the  pathological  condition  of  the  heat-regulating  mechan- 
ism is  essentially  the  same  in  both  cases,  it  is  due  to  different  causes, 
for  the  disturbance  produced  by  the  heat  puncture  is  a  direct  one, 
and  consequently  less  complicated,  while  the  alteration  of  this  func- 
tion in  fever  is  due  to  the  action  of  toxins  and  is  accompanied  by  all 
the  other  effects  of  the  infection. 

This  accounts  for  certain  differences  in  the  two  types  of  the  fever.      For 
example,  in  puncture  hyperthermia  primarily  non-nitrogenous  material  is  com-  ] 
busted,   apparently   chiefly   the   glycogen   of   the   liver   and   muscles    (Hirsch  u.  j 
Roily),  while  in  infectious  fever  it  is  principally  nitrogenous  material  rendered  ! 
available    by   the    pathological    decomposition    of    proteid    which    furnishes    the 
material    for    the    increased    combustion.      When   the    reserve    substances    have 


MECHANISM  OF  FEVER  461 

been  completely  consumed,  heat  puncture  causes  no  fever  (Hirsch) ,  a  fact 
which  has  been  interpreted  by  some  as  indicating  an  essential  difference  between 
it  and  true  fever.  However,  the  occurrence  and  extent  of  the  increased  com- 
bustion both  depend  upon  the  presence  of  readily  available  material,  which  in 
true  fever  is  always  available  in  the  form  of  nitrogenous  material  resulting 
from  the  decomposition  of  protoplasm,  although  ordinarily  such  material  is 
tenaciously  protected  in  fasting  and  emaciated  individuals. 

However,  this  difference  between  puncture  hyperthermia  and  infectious 
fever  is  not  a  fundamental  one,  for  in  fasting  animals  it  has  been  found  that 
no  rise  of  temperature  results  from  the  injection  of  albumoses  and  other 
pyrogenous  substances  which  ordinarily  cause  a  septic  fever  (Krehl  u.  Matthes). 

Consequently,  everything  speaks  for  the  assumption  that  the 
fever  of  infection  and  that  following  heat  puncture  are  due  to  a 
basically  similar  action  upon  the  heat-regulating  centres.  This 
parallelism  between  the  two  types  is  of  importance  for  our  under- 
standing of  the  pathology  of  fever  as  well  as  for  our  understanding 
of  the  action  of  the  antipyretics,  for  the  augmentation  of  the  tempera- 
ture following  the  heat  puncture  is,  without  any  doubt,  to  be  at- 
tributed to  the  trauma's  causing  a  stimulation  of  the  heat-regulating 
centres.  The  main  evidence  that  this  is  so  is  found  in  the  fact  that 
the  temperature  may  be  augmented  by  electric  stimulation  by  means 
of  electrodes  fixed  at  the  proper  place  in  the  corpus  striatum.  We 
may  then  conclude  that  the  alteration  of  the  heat  regulation  resulting 
from  heat  puncture  is  due  to  stimulation  or  irritation  of  these  centres, 
and  are  justified  in  assuming  the  same  for  fever.  When  we  say  then 
that  the  heat-regulating  mechanism  is  "  set  "  for  a  higher  tempera- 
ture, we  mean  that  the  heat-regulating  centres  are  in  a  condition  of 
pathologically  augmented  excitability. 

While  in  puncture  hyperthermia  this  excitation  is  produced  by 
mechanical  or  electrical  irritation,  in  infectious  fever  we  are  dealing 
with  an  irritation  produced  by  toxic  substances,  parallels  for  which 
may  be  found  in  the  various  other  symptoms  of  irritation  observed 
in  fever.  In  both  cases  the  excitability  of  the  heat-regulating  centres 
is  so  altered  that  they  react  so  as  to  conserve  heat  to  stimuli  which 
are  weaker  than  those  ordinarily  adequate, — i.e.,  this  reaction  occurs 
without  any  actual  cooling  of  the  body.  However,  in  a  normal 
reaction  to  cooling,  the  excitation  of  the  centres  lasts  only  as  long  as 
is  necessary  to  maintain  the  body  temperature,  but  when  their  excita- 
bility is  pathologically  increased  the  augmentation  of  metabolism 
and  the  limitation  of  heat  output  persist  until  that  degree  of  tempera- 
ture is  attained  at  which  the  sedative  action  of  the  increased  tem- 
perature of  the  blood  counterbalances  this.  When,  then,  in  the  course 
of  the  sickness  the  augmented  excitability  passes  off  again,  the  centres 
react  once  more  in  a  normal  fashion  to  the  overheated  blood,  so  that 
the  heat  output  is  again  augmented  until  the  normal  temperature  is 
regained. 

There  is  no  contradiction  between  this  conception  of  fever,  as  due  to  a  per- 
sistent abnormal  stimulation  of  the  heat- regulating  mechanism,  and  the  well- 
known  fact  that,  generally  speaking,  the  body  temperature  in  fever  is  more 


S""V 


462  PHARMACOLOGY  OF  HEAT  REGULATION 

unstable  than  in  health,  for  a  similar  behavior  of  irritated  organs  is  often 
enough  observed  (Loewi).  The  slighter  resistance  manifested  by  the  febrile 
organism  to  frigorific  influences  may  be  conceived  of  as  the  expression  of  the 
fact  that  the  irritated  centres  are  more  readily  fatigued. 

From  the  foregoing,  the  action  of  pyrogenous  substances  must  be 
attributed  to  a  stimulation  or  an  augmentation  of  the  excitability  of 
the  heat-regulating  mechanism.  Fever  results  from  the  invasion  of 
the  .pathogenic  organisms,  and  persists  as  long  as  the  body,  with  the 
assistance  of  its  defensive  weapons  (antitoxins,  bacteriolysins,  etc.), 
is  able  to  continue  the  battle;  but  when  it  succumbs,  collapse  de- 
velops and  the  temperature  falls.  It  consequently  appears  probable 
that  certain  substances,  which  are  formed  as  a  result  of  the  death 
of  the  pathogenic  organisms,  act  as  pyrogenic  poisons,  which  stimu- 
late the  heat-regulating  centres  and  in  larger  amounts  paralyze  them. 
Heterogeneous  proteid  also,  when  it  disintegrates  in  the  body,  causes 
a  rise  of  temperature,  which,  under  the  peculiar  conditions  of  hyper- 
susceptibility  to  heterogeneous  proteid,  expresses  itself  as  an  anaphy- 
lactic  fever.  Moreover,  the  decomposition  products  of  homologous 
cells — for  example,  the  albumoses — also  act  as  pyrogenetic  agents 
(Krehl  u.  Matthes).  Apparently  a  large  number  of  substances,  par- 
ticularly when  administered  intravenously  and  in  the  presence  of 
hypersusceptibility,  cause  a  septic  fever  by  causing  decomposition 
of  cells  or  of  proteid  (Krehl).  While  the  mechanism  by  which  this 
is  accomplished  has  not  been  cleared  up,  it  is  not  improbable  that 
a  stimulation  or  augmentation  of  the  excitability  of  the  sympathetic 
nervous  system,  to  which  consequently  the  heat-regulating  centres  also 
probably  belong,  plays  a  causative  role  in  the  production  of  such  fever. 

In  favor  of  this  view  is  the  fact  that  tetrahydronaphthylamine 
(see  p.  159)  has  a  marked  power  of.  raising  the  temperature  (B. 
Stern),  and  that,  moreover,  many  drugs,  like  caffeine,  cocaine,  and 
atropine,  which,  generally  speaking,  stimulate  many  of  the  nervous 
centres,  cause  an  increase  of  the  temperature,  even  quite  independently 
of  the  secondary  effects  of  any  convulsions  which  they  may  cause. 
These  are  all  drugs  which  cause  other  symptoms  of  stimulation  of 
the  sympathetic  or  depression  of  the  antagonistic  autonomic  system, 
such  as  pulse  acceleration,  mydriasis,  psychic  stimulation,  etc. 

That,  on  the  other  hand,  other  drugs  which  also  stimulate  various 
centres,  such  as  the  convulsant  poisons  like  santonin,  picrotoxin, 
aniline,  phenol,  etc.,  do  not  raise  the  temperature,  but  in  fact  under 
certain  conditions  markedly  depress  it  (see  p.  473),  does  not  speak 
against  such  a  conception,  but  rather  confirms  our  interpretation,  for 
these  drugs  do  not  stimulate  the  sympathetic  nerves,  but,  on  the 
contrary,  stimulate  the  antagonistic  autonomic  centres,  causing  slow- 
ing of  the  pulse,  miosis,  psychic  depression,  etc.  Finally,  moreover, 
the  typical  sympathetic  poison,  epinephrin,  can  under  certain  con- 
ditions cause  a  marked  augmentation  of  the  temperature  (Eppinger, 
Falta  u.  Rudinger),  and  it  appears  probable  that  this  epinephrin 


ANTIPYRETICS  IN  FEVER  463 

fever  is  due  to  a  central  or  peripheral  stimulation  of  the  sympathetic 
system.  In  the  fasting  animal  and  in  narcosis,  epinephrin  causes  no 
rise  in  temperature,  and  calcium  salts,  which  depress  the  excitability 
of  all  organs  which  are  susceptible  to  epinephrin,  also  prevent  or 
lower  fever  thus  caused  (Freund). 

According  to  this  last-mentioned  author,  sodium-chloride  fever 
is  of  a  similar  type.  This  was  first  observed  in  infants  after  the  ad- 
ministration of  large  quantities  of  common  salt  (Finkelstein,  Schloss], 
but  may  also  be  induced  in  adults  in  about  50  per  cent,  of  the  cases 
(Bingel],  and  even  more  readily  in  animals.  It  would  appear  that 
this  sodium-chloride  fever  is  also  due  to  stimulation  of  the  sympa- 
thetic nervous  system.* 

BIBLIOGRAPHY 

Bingel:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  G4. 

Colasanti:   Pfluger's  Arch.,  1877,  vol.  14,  p.  125.   'i'SV 

Eppinger,  Falta  u.  Rudinger :   2tschr.  f .  klin",  Med.,  vol.  66.  & 

Filehne:   Berl.-klin.   Woch.,   1882,^Np.   45;    1883,  No.  6. 

Filehne:   Kongress  f.  Innere  Medizin,   1885. 

Finkelstein;   Deut.  med.  Woch.,   1909,  p.  491. 

Finkler:   Pfliiger's  Arch.,  1882,  vol.  29,  p.  89.  *  /  .' 

F.reund:   Miinchn  med.   Woch.,   1911,   No.   0-.  /  ^  - 

.Geigel :,  Verhandl.  d.  Phys.-med.  Ges.,  Wiirzburg,  1889,  vol.  22,  No,  1. 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28,  p.  167. 

Hirsch  u.  Roily:   Deut.  Arch.  f.  klin.  Med.,  1903,  vol.  75,  p.  307. 

Kraus:   Wien.  klin.  Woch.,  1894,  p.  229. 

Krehl:   Patholog.  Physiol.,  4th  edition,  Leipzig,  1906. 

Krehl:  Arch.  f.  exp.  Path,  u.,  Pharm.,   1895,  vol.  35,  p.  222. 

Krehl  u.  Matthes:   Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36,  p.  451;  vol.  37, 

p.  232;   1897,  vol.  38,  p.  284.    >; 

Liebermeister :   Path.  d.  Fiebers,  Leipzig,  1875,  p.  341. 
Lilienfeld:   Pfluger's  Arch.,  1883,  vol.  32,  p.  293. 
Loewi :   Ergebnisse  d.  Physiol.,  1904,  vol.  3,  p.  332. 
Maragliano:   Ztschr.  f.  klin.  Med.,  1888,  vol.  14;    1890,  vol.  17. 
Richter:   Virchow's  Arch.,   1891,  vol.   123,  p.  118. 
Rosenthal,  C.:  Arch.  f.  Anat.  u.  Phys.,  1888,  p.  1. 
Schaps:   Berl.  med.  Woch.,  1907,  p.  597. 
Schloss:   Biochem.  Ztschr.,  vols.  17  and  22. 
Schultze:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  43,  p.  193. 
Stern,  R. :   Virchow's  Arch.,  1889,  vol.  115;  1890,  vol.  121. 
ern:   Ztschr.  f.  klin.  Med.,  1892,  vol.  20,  p.  63. 

ACTION  OF  ANTIPYRETICS   IN  FEVER 

The  conception  of  fever  as  caused  by  over-excitability  of  the  heat- 
regulating  centres  is  useful  in  explaining  the  antipyretic  effects  of 
certain  drugs,  in  considering  which  it  is  advantageous  to  use  as  a 
starting-point  the  simpler  fever  that  follows  puncture  (Gottlieb). 

If  the  fever  following  heat  puncture  in  the  rabbit  be  allowed  to 
run  its  course  without  interference,  the  curve  exhibits  the  char- 
acteristics of  continuous  fever. 

*  [As  a  result  of  recent  investigations  of  the  effects  of  the  intravenous  injec- 
tion of  normal  saline  solutions  made  up  with  freshly  distilled  water  as  con- 
trasted with  those  made  up  with  distilled  water  which  had  stood  some  time, 
considerable  doubt  has  been  thrown  on  the  earlier  experiments  which  appeared 
to  demonstrate  the  possibility  of  a  sodium  chloride  fever. — TB.] 


464 


PHARMACOLOGY  OF  HEAT  REGULATION 


After  the  preliminary  fall  of  the  temperature  due  to  the  shock  of 
the  operation,  the  fever  within  a  few  hours  rises  markedly,  and 
maintains  itself  without  marked  variation  for  12-24  hours  at  about 
41-42°  C,  and  then  very  gradually  returns  to  normal. 


h  3     *     S     6     7     8  9     to    n     12    t     Z     3     *     S     6  IO    ft   t2     1     Z    » 


FIGS.  56. — Normal  course  of  puncture  hyperthermia. 

In  other  particulars  such  rabbits  manifest  no  other  disturbances 
of  function,  and  continue  to  eat  and  appear  quite  normal.  A  dose  of 
antipyrine  causes  a  sharp  depression  in  this  very  regular  course  of 
the  temperature  curve. 

Without  producing  any  other  noticeable  effects,  0.5  gm.  of  antipyrine  ad- 
ministered to  such  a  rabbit  brings  the  temperature  back  to  normal,  but  after 
about  two  hours  the  temperature  commences  to  rise  again,  and  after  about  6-8 
hours,  when  the  effects  of  the  drug  have  passed  off,  regains  its  original  height. 

The  more  the  effects  of  the  puncture  in  causing  stimulation  of  the 
heat  centres  have  passed  off  before  the  antipyretic  is  administered, 
the  greater  is  the  effect  of  the  drug  in  bringing  about  a  changed 
"  setting  "  of  the  centre, — i.e.,  in  lessening  its  excitability.  Con- 
sequently, at  the  summit  of  the  temperature  curve  or  in  the  descend- 

h  7        8        9       TO      ff       IS       f        23         *        5        «         780 


•X4 

*/ 

*9 

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ine 

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--  —  ' 



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* 

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*•'    — 

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A 

*-*" 

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/ 

V 

^^ 

/ 

+ 

FIG.  57. — Effect  of  antipyrine  on  puncture  hyperthermia. 

ing  portion,  antipyrine  acts  more  strongly  than  during  the  period  in 
which  the  temperature  is  rising  rapidly.  The  other  drugs  belonging 
to  the  same  pharmacological  group  act  here  just  like  antipyrine. 

It  is  of  decisive  importance  for  the  interpretation  of  these 
phenomena  that,  on  the  one  hand,  the  puncture  hyperpyrexia  is 
conceived  of  as  due  to  stimulation  of  the  heat  centres  and  that,  on  the 
other  hand,  all  typical  antipyretics  are  narcotic  in  their  nature. 
Consequently  it  may  be  concluded  that  the  antipyretics  owe  their 


465 


action  to  their  power  of  acting  as  sedatives  to  the  pathologically 
stimulated  heat  centres.  If  any  further  proof  of  the  correctness  of 
this  conception  were  necessary,  this  is  furnished  by  the  observation 
that  other  drugs  which  without  any  doubt  act  as  central  depressants — 
for  example,  small  doses  of  morphine — lower  the  temperature  of 
puncture  hyperthermia,  even  in  the  rabbit,  which  is,  generally  speak- 
ing, very  insusceptible  to  this  drug. 


July  lH 
h   JO  J1J2    1234967 


July  13 
fO   //  f2   1    2     3    4    S    6 


39 


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dantip. 

/riste 

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92morf 

>A  hycb 

ochlor. 

/" 

3; 

t 

r* 

\ 

/ 

\ 

\. 

z 

I 

\ 

>1 

y 

V 

^^ 

/ 

\ 

/ 

\ 

^ 

/ 

\, 

V 

FIG.  58. — Effects  of  morphine  and  of  antipyrine  on  puncture  hyperthermia. 

The  antipyretics  consequently  are  narcotics  of  the  heat-regulating 
centres  of  the  brain.  Their  basic  narcotic  character,  however,  does 
not  show  itself  solely  in  their  sedative  action  on  the  heat-regulating 
mechanism,  for  their  mild  depressing  action  is  just  as  clearly  mani- 
fested in  the  sensory  portion  of  the  cerebral  cortex.  Consequently 
the  more  powerful  antipyretics  cause  a  more  or  less  pronounced  con- 
dition of  sleepiness  and  of  diminished  sensibility  in  laboratory  ex- 
periments. Above  all,  however,  clinical  experience  has  taught  us 
that  all  the  antipyretics  are  at  the  same  time  analgesics  and  seda- 
tives,— i.e.,  mild  narcotics  for  the  sensory  cerebral  tracts. 

From  what  has  already  been  stated,  it  is  clear  that  the  com- 
bination of  antipyretic  and  sedative  action  in  all  the  drugs  of  this 
group  is  not  merely  a  coincidence,  for  both  of  these  properties  are 
the  expression  of  a  mild  narcotic  action  on  the  cerebrum,  the  elective 
seats  for  this  action  being  assumed  to  lie,  on  the  one  hand,  in  the 
cerebral  cortical  centres  for  the  perception  of  pain  (just  as  is  the  case 
with  morphine)  and,  on  the  other  hand,  in  the  heat-regulating  cen- 
tres which  are  over-stimulated  in  fever.  For  these  reasons  Schmiede- 
berg  has  very  appropriately  given  to  the  drugs  of  the  antipyrine  group 
the  name  of  fever  narcotics.  This  name,  moreover,  correctly  character- 
izes this  group  of  drugs,  inasmuch  as  modern  medicine  employs  them 
in  fever  but  seldom  as  a  means  of  combating  the  hyperpyrexia  as 
such,  but  rather  in  the  hope  that  the  patient  will  be  benefited  by  their 
sedative  action  on  all  those  symptoms  of  fever  which  are  due  to  over- 
excitability  of  the  centres. 

It  is  quite  in  accord  with  the  conception  of  the  antipyretics  as 
sedatives  of  the  heat  centres  that  those  doses  which  are  effective  in 
fever  do  not  influence  the  temperature  in  health,  although  larger  doses 


30 


466  PHARMACOLOGY  OF  HEAT  REGULATION 

do  produce  a  lowering  of  the  temperature  even  in  health.  The  ex- 
planation of  the  stronger  effect  on  the  excitable  heat  centres  of  fever 
is  found  in  the  general  experience  that  nervous  centres,  when  in  a 
condition  of  persistent  over-excitability,  are,  as  a  rule,  more  readily 
fatigued,  and  consequently  more  susceptible  to  the  action  of  narcotics. 
The  same  thing  is  observed  to  a  very  striking  extent  in  the  physio- 
logical effects  of  strychnine,  in  which  over-excitability  and  ready 
exhaustibility  of  the  reflex  centres  go  hand  in  hand. 

The  therapeutic  action  of  the  antipyretics  as  described  thus  far 
should,  however,  be  clearly  differentiated  from  a  true  paralysis  of  the 
heat-regulating  mechanism,  for,  after  effective  doses  of  antipyrine, 
animals  still  react  very  decidedly  to  changes  in  the  external  tempera- 
ture, although  not  so  promptly  as  untreated  controls.  The  power  of 
regulating  the  body  temperature  is  lost  only  after  very  much  larger 
doses,  this  being  simply  one  of  the  results  of  the  general  collapse 
which  is  caused  by  larger  doses. 

COLLAPSE. — Numerous  poisons  and  drugs  cause  collapse  with  a  marked 
fall  of  blood-pressure,  both  effects  being  the  result  of  a  commencing  paralysis 
of  the  vital  centres.  Particularly  with  the  narcotic  drugs  and  poisons  the 
therapeutically  effective  doses  lie  relatively  near  to  those  which  cause  col- 
lapse. Like  the  narcotics,  substances  of  the  carbolic  acid  group,  the  salicy- 
lates,  and  members  of  the  antipyrine  group,  all  of  which  are  closely  related 
pharmacologically,  produce  such  conditions  of  paralysis  relatively  easily.  In 
such  collapse  the  temperature  of  the  body  falls,  but  this  lowering  of  the 
temperature  by  depressing  the  various  nervous  centres  differs  from  the  elective 
antipyretic  action  in  its  entirely  different  symptomatology  and  in  the  different 
manner  in  which  it  is  produced.  In  collapse,  as  the  temperature  falls,  the 
pulse  becomes  small  and  weak,  the  extremities  grow  cold,  and  all  those 
symptoms  develop  which  are  spoken  of  as  cardiac  weakness.  As  a  result 
of  depression  of  the  vasomotor  centres,  the  rapidity  of  the  blood  circulation 
is  so  diminished  that  only  small  amounts  of  heat  are  lost  through  the  skin, 
and  at  the  same  time  the  heat  production  is  diminished  as  a  result  of  a 
centrally  induced  diminution  of  heat  production  (Krehl  u.  Matthes). 

There  is  no  doubt  that  a  number  of  drugs  formerly  much  used  in  fever — 
for  example,  veratrum  and  aconite — produce  a  narcotic  effect  on  the  over- 
excited heat-regulating  centres  similar  to  that  produced  by  our  modern  anti- 
pyretics. However,  they  differ  from  these  latter  in  that  their  actions  are 
not  so  electively  confined  to  the  heat-regulating  mechanism,  and,  as  a  con- 
sequence, with  them  antipyretic  effects  result  only  from  such  doses  as  lie  very 
close  to  the  dangerous  ones  which  may  cause  collapse.  As  a  consequence,  these 
drugs  have  been  abandoned,  and  correctly  so  (see  pp.  109,  426). 

Pyrogenic  poisons  also  very  readily  cause  collapse,  causing  in 
small  doses  an  augmentation  and  in  larger  doses  a  fall  of  the  tem- 
perature, which  is  accompanied  by  a  diminution  of  both  the  produc- 
tion and  the  output  of  heat  (Krehl  u.  Matthes').  Fever  may,  there- 
fore, be  considered  as  a  symptom  of  stimulation  produced  by  small 
amounts  of  toxins,  and  collapse  as  a  symptom  of  the  paralysis  caused 
by  larger  amounts  of  these  substances. 

BIBLIOGRAPHY 

Gottlieb:   Arch.  r.  exp.  Path.  u.  Pharm.,  1890,  vol.  26,  p.  419. 
Krehl  u.  Matthes:   Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  299. 
Schmiedeberg :  Grundriss   d.   Pharmakol.,   Leipzig.,    1909. 


COLD  BATHS  467 

COLD  BATHS 

Following  the  discussion  of  the  more  pronounced  alterations  of 
febrile  temperature  produced  by  antipyretic  drugs,  the  entirely  anal- 
ogous action  of  cold  baths  should  be  briefly  considered. 

The  temperature  of  a  healthy  individual  does  not  fall  at  all  as 
a  result  of  such  moderate  abstraction  of  heat  as  results  from  ordinary 
hydrotherapeutic  measures.  In  fact,  at  the  start  the  internal  tem- 
perature rises  for  a  short  time  (Llebermeister} ,  because,  by  the  con- 
traction of  the  cutaneous  vessels,  the  blood  is  driven  out  from  the 
region  in  which  normally  it  is  cooled,  and  it  is  only  during  the  so- 
called  primary  after-effect  that  the  temperature  may  fall  slightly, 
if  after  the  bath  the  cutaneous  vessels  relax  so  that  larger  than 
normal  amounts  of  blood  may  flow  through  the  cooled-off  skin.* 
Under  normal  conditions,  the  physical  regulation  by  constriction  of 
the  cutaneous  vessels  and  the  chemical  regulation  by  increased  com- 
bustion of  non-nitrogenous  substances  are  sufficient  to  keep  the  tem- 
perature of  the  body  constant  within  very  narrow  limits.  However, 
the  power  of  heat  regulation,  even  in  health,  has  a  limit,  and  the 
temperature  of  the  body  sinks  if  the  temperature  of  the  bath 
is  extremely  low  and  its  duration  very  long,  this  occurring  more 
readily  in  small  and  poorly  nourished  than  in  large  and  fat  indi- 
viduals. 

In  the  febrile  patient,  on  the  other  hand,  the  temperature  is  much 
more  markedly  lowered  even  by  very  moderate  cooling,  and  often 
remains  somewhat  depressed  for  hours.  It  is  thus  evident  that  in 
fever  the  heat  regulation  exhibits  the  same  instability  in  its  reaction 
to  measures  by  which  heat  may  be  abstracted  as  to  medicinal  anti- 
pyretics. Just  as  with  antipyrine,  the  heat  production  in  a  febrile 
individual  is  augmented  to  a  slighter  degree  by  abstraction  of  heat 
than  is  the  case  in  health.  Particularly  in  the  period  of  after-action, 
in  which  the  diminution  of  the  temperature  becomes  more  pronounced, 
the  chemical  heat  regulation  of  the  febrile  patient  more  readily  proves 
itself  insufficient.  This  effect  is  augmented  further  by  the  fact  that 
in  many  febrile  conditions  the  vasomotor  centres  tire  particularly 
easily,  so  that,  after  being  contracted  during  the  bath,  in  the  after- 
period  the  tone  of  the  cutaneous  vessels  is  markedly  diminished  and 
for  a  considerable  period  (Krelil}* 

BIBLIOGRAPHY 
Krehl:  Patholog.  Physiol. 
Liebermeister:   Pathologic  d.  Fiebers. 

*  [Such  reaction  is  favored  by  continuous  friction  of  the  body  during  the  bath. 
That  this  is  so  may  be  readily  demonstrated  by  comparing  the  after-effects  on  the 
temperature  produced  by  baths  given  with  such  friction,  with  those  following 
similar  baths  given  without  it. — TB.] 


468  PHARMACOLOGY  OF  HEAT  REGULATION 


DIRECT  ACTIONS  OF  THE  ANTIPYRETICS  ON  HEAT  PRODUC- 
TION AND  HEAT  LOSS 

Thus  far  we  have  spoken  as  if  only  the  central  heat-regulating 
mechanism  were  affected  by  the  antipyretics.  On  closer  examination, 
however,  the  conditions  are  found  to  be  more  complicated.  This  is 
dependent  on  the  fact  that  the  action  of  the  antipyretics  is  not  limited 
to  the  heat-regulating  centres  alone,  but  that  certain  of  them  also 
affect  the  heat  economy  of  the  body  by  influencing  the  output  or 
formation  of  heat  independently  of  the  central  regulating  mechanism. 
From  this  point  of  view  we  may  differentiate  between  two  groups  of 
antipyretics : 

Those  of  the  antipyrine  group,  which  cause  cutaneous  vasodilata- 
tion  and  directly  increase  the  heat  loss;  and 

Quinine,  which  lessens  the  production  of  heat  by  a  direct  action 
on  the  various  metabolic  processes  in  the  tissues.  The  phenomena  of 
defervescence,  as  it  actually  occurs,  are  in  part  due  to  these  direct 
actions  on  the  functions  of  heat  output  and  heat  production. 

ACTION  OF  THE  ANnPYRINE  GROUP  ON  THE  HEAT  OUTPUT 

If  antipyrine  acted  only  on  the  central  heat  regulation,  and 
changed  the  over-excitability  of  the  centres  to  a  normal  condition  with- 
out directly  and  independently  interfering  with  the  heat  economy  of 
the  body,  it  should  be  expected  that  under  its  influence  the  body  would 
get  rid  of  its  superfluous  heat  in  the  same  fashion  as  in  spontaneous 
defervescence.  In  spontaneous  reduction  of  the  temperature  the  pro- 
duction of  heat  is  reduced  to  the  normal  or  even  below  this  (Krehl  u. 
Matthes),  but,  above  all,  the  output  of  heat  is  so  influenced  that 
critical  defervescence  in  infectious  diseases  is  followed  by  marked 
dilatation  of  the  cutaneous  vessels  and  profuse  sweating.  The  same 
phenomena  then  should  occur  if  a  dose  of  antipyrine  has  brought 
about  a  normal  condition  of  the  heat  centres,  and,  as  a  matter  of  fact, 
in  defervescence  produced  by  antipyrine  the  behavior  of  the  organism 
corresponds  in  many  cases  to  this  type  (Stuhlinger). 

However,  it  does  not  always  do  so,  for  antipyrine  possesses  the  power 
of  dilating  the  cutaneous  vessels  independently  of  the  heat-regulating  mechanism 
and  to  an  even  greater  degree,  and  even  in  health  this  effect  may  be  produced 
by  doses  which  do  not  lower  the  temperature,  and  which  consequently  are 
incapable  of  affecting  the  tone  of  the  more  resistant  heat-regulating  centres  of 
the  healthy  individual.  As  a  result  of  this  cutaneous  vasodilatation,  antipyrine 
increases  the  heat  loss  in  health  as  well  as  in  fever.  That  the  temperature 
does  not  fall  is  due  to  a  compensatory  augmentation  of  the  heat  production, 
which  opposes  the  alteration  of  the  temperature  as  long  as  the  heat-regulatory 
mechanism  is  capable  of  functioning  normally  (Gottlieb).  This  compensatory 
augmentation  of  combustion  is  the  explanation  for  the  often  considerably  in- 
creased excretion  of  nitrogen  which  antipyrine  and  related  substances  cause 
in  healthy  men  in  whom  the  heat  regulation  acts  promptly. 

While  in  the  healthy  man  this  prompt  regulation  of  temperature  is  over- 
come only  by  much  larger  doses  than  are  used  therapeutically,  in  fever  such 


ANTIPYRINE  GROUP 


469 


doses  of  antipyrine  do  weaken  this  regulatory  function,  and,  as  a  consequence, 
there  is  no  longer  so  great  an  increase  in  the  heat  production  as  there  is  in 
the  heat  loss,  and  consequently  the  body  temperature  falls. 

This  attempt  of  the  organism  to  combat  the  augmented  heat  loss  caused 
by  antipyrine  is  also  manifested  in  many  cases  of  fever  when  the  temperature 
falls,  causing,  just  as  in  the  healthy  individual,  a  compensatory  augmentation 
of  heat  production,  which  is  not  to  be  disregarded,  for  it  necessarily  results  in 
an  increased  consumption  of  tissues.  This  regulation  against  heat  loss  is,  it 
is  true,  often  but  slight  in  febrile  patients  (Riethus),  and  consequently  the 
diminution  of  heat  production  which  results  from  the  defervescence  more  than 
counterbalances  it.  The  reduction  of  febrile  temperature  by  antipyrine  may 
be  schematically  represented  in  the  accompanying  diagram. 


Body  temperature 


-38" 


-370 


Commencement  of 
antipyrine  action 


Cessation  of 
antipyrine  action 


-36° 


Fever 


-Heat  production 
—  —  —  —*Heat  loss 

FIG.  59. — Antipyretic  effect  of  antipyrine.    Augmentation  of  heat  loss  with 
slight  compensatory  increase  in  heat  production. 

Antipyrine  and  related  substances  consequently  reduce  the  tem- 
perature principally  by  augmenting  the  heat  loss,  as  is  indicated 
by  the  simple  direct  observation  of  the  hot  and  reddened  skin  and  as 
has  been  demonstrated  thermoelectrically  by  Geigel  and  plethysmo- 
graphically  by  Maragliano.  This  cutaneous  vasodilatation  is  not 
simply  one  symptom  of  a  generally  diminished  vascular  tone,  but  is 
the  result  of  an  antagonistic  behavior  of  the  vessels  of  the  skin  and 
those  of  the  internal  organs.  As  this  does  not  lower  the  general 
blood-pressure,  and  may  in  fact  increase  it,  large  quantities  of  blood 
are  caused  to  flow  through  the  dilated  vessels  on  the  surface  of  the 
body,  where  the  fever-heated  blood  has  an  opportunity  to  give  off  its 
superfluous  heat,  this  bringing  about  an  increase  in  the  heat  output, 
which  has  been  demonstrated  both  in  animals  (Gottlieb  u.  Richter) 
and,  by  partial  calorimetry,  in  man  (Rosenthal). 

It  must  again  be  emphasized  that  the  above-described  augmenta- 
tion of  the  heat  loss  is  not  the  true  cause  of  the  antipyretic  action  of 
antipyrine,  for  the  augmentation  of  heat  loss,  which,  according  to 
calorimetric  determinations,  seldom  exceeds  the  normal  by  more  than 
20-30  per  cent.,  is  much  too  slight  to  overcome  a  normally  functioning 
heat  regulation.  Consequently,  in  a  healthy  man  the  temperature  is 
not  altered,  in  spite  of  such  increased  heat  output,  but,  owing  to 
the  greater  ease  with  which  the  over-stimulated  and  at  the  same  time 


470 


PHARMACOLOGY  OF  HEAT  REGULATION 


readily,  fatigued  centres  of  fever  may  be  influenced,  even  smaller 
doses  are  sufficient  to  produce  a  sedative  effect  on  the  heat-regulating 
centres.  This  sedative  action  on  the  central  heat  regulation  is  to 
be  considered  as  the  real  cause  of  the  antipyresis,  while  the  directly 
produced  augmentation  of  the  heat  loss  is  to  be  regarded  simply  as 
a  simultaneous  clearing  of  the  paths  by  which  the  superfluous  heat 
is  eliminated. 

BIBLIOGRAPHY 

Geigel:  Verb.  d.  Physik.-med.  Ges.,  Wiirzburg,  1889,  vol.  22,  No.  1. 

Gottlieb:   Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28,  p.  167. 

Krehl  u.  Matthes:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  284. 

Maragliano:  Ztschr.  f.  klin.  Med.,  1880,  vol.  14,  p.  309. 

Eichter:   Virchow's   Arch.,    1891,   vol.    123. 

Eiethus:   Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  47,  p.  240. 

Eosenthal,  C.:  Dubois'  Arch.,  1888,  p.  1. 

Stiihlinger:  Arch.  f.  exp.  Path.  u.  Pharm.,  1899,  vol.  43,  p.  167. 

ACTION   OF   QUININE   ON   HEAT   PRODUCTION 

The  temperature  in  healthy  men  and  animals  is  either  not  dimin- 
ished at  all  or  only  very  slightly,  even  by  doses  of  quinine  much  larger 
than  those  which  are  effective  in  fever  (Stuhlinger).  In  fact,  after 
smaller  doses  the  temperature  not  infrequently  rises  (Jansen,  Fried- 
mann) ,  a  paradoxical  effect  which  may  be  produced  by  other  antipy- 
retics and  for  which  no  satisfactory  explanation  can  be  given. 

If  the  action  of  quinine  is  studied  on  animals  in  the  calorimeter, 
it  may  be  demonstrated  that  the  fall  in  the  body  temperature  is 
chiefly  the  result  of  a  limitation  of  the  heat  production  (Gottlieb} 
while  at  the  same  time  the  heat  loss  is  augmented  to  a  slight  degree. 
The  reduction  of  fever  caused  by  quinine,  consequently,  may  be 
diagrammatically  represented  as  follows: 


emperature 


Commencement  of 
action  of  quinine 
Fever        ^ 


End  of  action 
of  quinine 


-38<> 
-37» 
-SCO 


Fever 


—  H eat  production 
— -  — — —  Heat  loss 

FIQ.  60. — Antipyretic  effect  of  quinine.    Heat  production  diminished 
and  heat  loss  slightly  increased. 

The  limitation  of  heat  production  by  quinine  is  a  primary  or  direct  action, 
occurring  even  after  separation  of  the  body  from  the  heat-regulating  centres 
by  section  of  the  cord.  Krehl  and  Hatthes  investigated  the  behavior  of  the 
temperature  of  rabbits  thus  prepared  at  the  temperature  of  27°  C.,  and  found 
that  quinine  *  under  such  conditions  caused  a  marked  diminution  in  the 
amount  of  heat  formed,  while  antipyrine  produced  no  effect  whatever.  This 

*  See,  in  this  connection,  Naunyn  u.  Quincke  and  Binz. 


QUININE  471 

indicates  that  antipyrine  acts  upon  the  heat  economy  only  through  the  central 
nervous  system,  while  quinine,  even  after  the  elimination  of  all  central  nervous 
influences,  diminishes  the  metabolism  of  the  tissues.  In  agreement  with  this, 
quinine  also  lessens  the  production  of  heat  in  surviving  organs,  as  shown  by 
Bins's  observations  that  after  section  of  the  cervical  cord  no  post-mortem  rise 
of  temperature,  or  only  a  very  slight  one,  occurs  in  rabbits  which  have  taken 
quinine,  even  though  heat  loss  be  prevented,  although  in  the  controls  there  was 
a  very  marked  post-mortem  rise. 

In  a  similar  fashion,  the  addition  of  small  amounts  of  quinine  to  the  blood 
inhibits  the  usual  formation  of  acid  (Bins),  as  also  the  synthesis  of  hippuric 
acid  in  the  surviving  kidney  (A.  Hoffmann),  and  probably  other  syntheses  and 
decompositions  (Laqtieur)  in  the  tissues  are  inhibited  by  quinine,  perhaps  by 
inhibition  of  the  intracellular  ferments  by  quinine  (see  Metabolism,  p.  403),  so 
that  the  heat  production  in  the  tissues  is  directly  inhibited. 

However,  it  cannot  be  concluded  that  the  antipyretic  action  of 
quinine  is  entirely  the  result  of  this  action  on  the  metabolism,  for,, 
even  though  the  total  result  of  the  heat-producing  processes  is 
diminished  by  quinine,  this  diminution  is  always  so  slight  that  it 
could  be  readily  compensated  for  by  an  appropriate  increase  of  the 
heat  loss  if  the  heat-regulating  mechanism  were  functioning  normally. 
The  reduction  of  fever  produced  by  quinine  must,  consequently,  have 
still  another  cause,  which,  in  those  cases  in  which  its  action  is  not  a 
specific  one  as  it  is  in  malaria,  is  found  in  an  action  analogous  to 
that  of  antipyrine, — i.e.,  in  a  sedative  action  on  the  heat-regulating 
centres^  However,  this  central  action  of  quinine  is  less  powerful 
ftEaiTthat  of  the  antipyrine  group,  a  fact  which  is  demonstrated  by 
the  relatively  weak  action  of  quinine  in  puncture  hyperthermia.  In 
this  condition  the  temperature  is  lowered  by  quinine  only  in  the 
descending  portion  of  the  temperature  curve,  when  the  hyperthermia 
already  of  its  own  accord  shows  a  tendency  to  abate.  It  is  thus  evi- 
dent that  quinine  acts  much  less  energetically  on  the  function  of  heat 
regulation  than  does  antipyrine  (Gottlieb],  and,  consequently,  it  too 
in  non-toxic  doses  hardly  lowers  the  temperature  in  health,  and  exerts 
an  antipyretic  effect  only  when  the  heat-regulating  function  has  be- 
come abnormally  susceptible, — i.e.,  only  in  fever. 

The  reduction  of  temperature  induced  by  quinine  results,  just  as 
in  normal  defervescence,  from  augmentation  of  the  heat  output  and 
diminution  of  its  production.  Quinine  consequently,  as  a  result  of 
its  slight  action  on  the  heat-regulating  centres,  also  aids  spontaneous 
defervescence,  which  effect  is  aided  by  the  direct  diminution  of  heat 
production  resulting  from  its  action  on  the  metabolism,  and,  as  quinine 
primarily  limits  proteid  metabolism,  it  aids  the  organism  in  con- 
serving its  most  valuable  material. 

However,  by  no  means  all  fevers  may  be  successfully  combated 
with  moderate  doses  of  quinine.  The  more  marked  effect  of  quinine 
in  certain  infectious  fevers, — i.e.,  in  typhoid  (Erb}* — is  perhaps  due 
to  a  direct  action  on  the  cause  of  the  fever,  resembling  its  specific 
action  on  the  malarial  organisms  (see  Etiotropic  Agents,  p.  527). 

*  [This  is  certainly  doubtful.— TB.] 


472  PHARMACOLOGY  OF  HEAT  REGULATION 

BIBLIOGRAPHY 

Binz:  Virchow's  Arch.,  1870,  vol.  51,  p.  152.. 

Binz:  Arch.  f.  exp.  Path.  u.  Pharm.  1873,  vol.  1,  p.  18. 

Erbj  W.:  Therapie  d.  Gegenwart,  January,   1901. 

Friedmann:  Inaug.-Diss.,  Erlangen,  1890. 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  26,  p.  419. 

Gottlieb:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28,  p.  167. 

Hoffmann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1877,  vol.  7,  p.  233. 

Jansen:   Inaug.-Diss.,  Dorpat,  1872. 

Laqueur:  Arch.  f.  exp.  Path.  u.  Pharm.,  1906,  vol.  55,  p.  240. 

Naunyn  u.  Quincke:  Arch.  f.  Anat.  u.  Physiol.,  1869,  p.  571. 

Stiihlinger:  Arch.  f.  exp.  Path.  u.  Pharm.,   1899,  vol.  43. 

THE  SALICYLATES 

Salicylic  acid  apparently  occupies  a  position  between  quinine  and 
the  antipyrine  group.  In  common  with,  quinine,  it  appears  to  have 
the  property  of  acting  directly  on  the  cause  of  the  fever  in  acute 
articular  rheumatism  and  in  many  other  infections,  and,  like  it, 
salicylic  acid  too  has  comparatively  little  effect  on  puncture  hyper- 
thermia.  In  these  particulars  it  stands  close  to  quinine  and  in  a 
certain  opposition  to  the  antipyretics  which  act  purely  symptomati- 
cally. 

On  the  other  hand,  salicylic  acid  stands  closer  to  antipyrine  in 
respect  to  the  manner  in  which  it  lowers  the  temperature  in  fever. 
Particularly  in  those  conditions  in  which  it  acts  only  on  the  fever 
and  not  on  the  cause  of  the  disease,  it  not  only  does  not  lessen 
proteid  metabolism  but,  on  the  contrary,  very  markedly  increases  it 
(Kumagawa,  Virchow,  Salome,  etc.).  The  reduction  of  febrile  tem- 
perature by  salicylic  acid  is  due,  as  is  the  case  with  the  antipyrine 
group,  to  an  augmentation  of  heat  loss,  particularly  as  a  result  of 
sweating,  and  the  later  rise  of  the  temperature  may  often  actually 
be  accompanied  by  a  chill.  However,  the  behavior  of  the  heat 
economy  of  the  body  under  the  influence  of  the  salicylates  has  not 
been  sufficiently  studied  to  permit  of  a  closer  knowledge  of  its 
details. 

Acetyl-salicylic  acid,  introduced  by  Dreser  under  the  name  of 
aspirin,  appears  to  stand  much  nearer  to  the  antipyrine  group.  It 
lowers  the  temperature  caused  by  the  heat  puncture  much  more 
strongly,  and  is  consequently  more  effective  as  a  purely  symptomatic 
antipyretic  than  is  salicylate  of  soda  (Bondi  u.  Katz).  Although 
aspirin  is  excreted  only  after  being  decomposed,  it  may  be  absorbed 
without  undergoing  decomposition,  for  this  occurs  but  slowly  in  the 
intestine.  Consequently,  before  it  is  decomposed  with  the  formation 
of  salicylic  acid  by  the  ferments  of  the  tissues,  it  may  be  differently 
distributed  and  produce  other  actions  than  its  mother  substance. 

BIBLIOGRAPHY 

Bondi  u.  Katz:   Ztschr.  f.  klin.  Med.,  1910,  vol.  72,  p.  177. 

Dreser:   Pflilger's  Arch.,  1899,  vol.  76. 

Kumagawa:   Virchow's  Arch.,  1888,  vol.  113. 

Salome:   Wien.  med.  Jahrbiicher,  1885. 

Virchow,  C.:  Zeitschr.  f.  physiol.  Chemie,  1881,  vol.  6. 


SALICYLATES  AND  OTHER  ANTIPYRETICS          473 


Many  other  substances  also  possess  the  power  of  depressing  the 
temperature.  In  general  this  power  is  a  characteristic  of  many 
benzol  derivatives, — for  example,  of  carbolic  acid,  which  may  serve 
as  a  prototype  of  the  aromatic  antiseptics  (Harnack}.  While  the 
antipyretic  action  of  phenol  may  not  be  utilized  therapeutically  be- 
cause of  its  other  toxic  actions,  and  while  other  substances  chemically 
closely  resembling  carbolic  acid  (hydroquinine,  etc.)  are  too  poisonous 
and  often  produce  collapse,  various  aniline  and  paramidophenol 
derivatives,  formed  by  introduction  of  acids  into  their  molecules,  are 
comparatively  non-toxic  antipyretics. 

As  a  part  of  their  general  narcotic  action,  moreover,  many  nar- 
cotics of  the  alcohol  group,  in  particular  alcohol  itself,  exert  a  seda- 
tive action  on  the  heat-regulating  centres,  and  in  large  doses  paralyze 
them,  so  that  collapse  with  a  marked  fall  of  body  temperature 
develops. 

On  the  other  hand,  it  has  long  been  known  that  the  powerful  central 
stimulant  camphor,  when  given  in  large  doses,  lowers  the  temperature  in  fever 
(Hoffmann).  Harnack  and  his  collaborators  have  also  found  that  other  con- 
vulsants,  particularly  picrotoxin  and  santonin,  may  also  lower  the  body  tem- 
perature independently  of  any  convulsions  which  they  may  cause.  The  same 
is  true  for  aniline,  which  also  possesses  a  convulsant  action  ( Schuchardt ) . 
Moreover,  the  combination  of  santonin  or  picrotoxin  with  chloral,  amylene 
hydrate,  ether,  or  chloroform,  etc.,  which  of  themselves  possess  but  slight 
power  to  lower  temperature,  produces  a  tremendous  fall  in  the  temperature, 
which  is  much  larger  than  is  accounted  for  by  the  sum  of  the  effects  of  each 
of  these  components.  Evidently,  while  both  of  these  groups  of  antithermic  drugs 
act  on  the  heat-regulating  centres,  their  points  of  action  are  certainly  different, 
as  is  evidenced  by  the  different  behavior  of  the  temperature  when  cocaine  is 
administered  to  animals  in  which  the  temperature  has  been  lowered  by  some 
member  of  one  or  the  other  of  these  groups  (Harnack  u.  Schwedmann ) . 

BIBLIOGRAPHY 

Harnack,  E.:  Miinchn.  med.  Woch.,  1910,  No.  37. 

Harnack:   Ztschr.  f.  klin.  Med.,  1896,  vols.  24  and  25. 

Harnack:   Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  38;   1891,  vol.  39;   1892,  vol. 

45;  1893,  vol.  49. 

Harnack  u.  Schwedmann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  40,  p.  151. 
Hoffmann:   Inaug.-Diss.,  Dorpat,  1866. 
Schuchardt:   Arch.  d.  Pharmazie,  1861. 

THERAPEUTIC  EMPLOYMENT  OF  THE  ANTIPYRETICS 
Up  to  a  few  years  ago  physicians  believed  that  it  was  necessary 
to  give  antipyretics  in  the  presence  of  any  marked  febrile  augmen- 
tation of  the  temperature.  This  routine  endeavor  to  combat  fever 
was  due  to  theoretical  conceptions  which,  ever  since  the  middle  of  the 
last  century,  have  led  to  the  assumption  that  the  anatomical  alter- 
ations observed  in  the  parenchymatous  organs  after  severe  infection 
were  produced  by  long-continued  high  temperature.  (In  this  con- 
nection see  Krehl.)  Hence  the  fear  of  fever.  The  introduction  of 
the  modern  antipyretics,  which  permit  the  prompt  reduction  of  tem- 
perature without  producing  harmful  side  effects,  was  a  welcome  aid 


474  PHARMACOLOGY  OF  HEAT  REGULATION 

in  this  endeavor  to  combat  fever,  for  by  their  use  it  was  possible 
to  cause  even  such  a  disease  as  typhoid  to  run  its  course  without 
fever. 

However,  it  was  just  this  energetic  employment  of  antipyresis 
which  has  taught  us  that  by  no  means  all  the  supposed  dangers  of 
fever  are  due  to  the  augmentation  of  the  temperature  as  such,  and 
to-day,  as  a  result  of  the  experimental  investigations  of  Naunyn, 
Pfliiger,  Finkler,  Unverricht,  and  others,  it  is  known  that  these 
pathological  changes  are  not  the  results  of  the  increased  temperatures, 
but  that  they  are  a  coordinate  effect,  which,  like  the  alterations 
in  the  function  of  heat  regulation,  is  dependent  upon  the  intoxication 
produced  by  the  specific  infectious  poisons. 

The  augmentation  of  the  temperature  is  a  reaction  of  the  central 
nervous  system  to  its  invasion  by  these  poisons,  and  is  thus  a  symptom 
of  which  we  cannot  decide  a  priori  whether  it  be  harmful  or  useful 
to  the  organism.  In  more  recent  times  the  conviction  has  gained 
ground  that  fever  as  such  is  harmless,  and  we  have  been  more  and 
more  inclined  to  the  view — which,  by  the  way,  is  hundreds  of  years 
old — that  the  rise  of  temperature  represents  a  curative  effort  of 
nature, — i.e.,  that  it  is  a  defensive  reaction  of  the  diseased  organism, 
which  is  useful  to  it  in  its  struggle  with  the  cause  of  the  disease  and 
of  the  fever.  In  many  particulars  present  investigations  support  this 
view,  for  augmentation  of  the  body  temperature  by  overheating 
(Filehne,  Walther,  Rovighi)  or  by  heat  puncture  (Loewy  u.  Richter) 
appears  to  exert  a  favorable  influence  on  the  course  of  experimentally 
induced  infections. 

In  what  fashion  such  high  temperatures  produce  their  favorable 
effects  is  not  entirely  clear,  but  it  is  less  probably  due  to  a  direct 
effect  upon  the  growth  and  virulence  of  the  bacteria  than  to  the 
effect  of  the  increased  temperature  in  augmenting  combustive  pro- 
cesses and  in  producing  a  more  active  formation  of  the  various  pro- 
tective substances  (Kast,  Krehl,  Roily,  Meltzer,  Liidke).  Thus,  for 
example,  it  has  been  shown  that,  when  the  formation  of  antibodies  had 
already  become  less  active,  the  amount  of  these  substances  in  the 
blood  of  infected  rabbits  increased  again  if  their  temperature  was 
raised  by  heat  puncture  (Aronsohn  u.  Citron). 

Consequently,  it  is  not  the  augmentation  of  temperature  as  such 
which  should  be  combated,  but  only  certain  accompanying  phenomena. 
Among  these  it  is  certain  that  the  accelerated  action  of  the  heart, 
the  dyspno3a,  and  at  least  a  portion  of  the  augmentation  of  metabolic 
processes  are  to  be  considered  as  due  to  the  abnormal  temperature, 
and,  in  case  of  excessive  hyperpyrexia,  these  may  become  distinctly 
dangerous  to  the  patient.  Consequently  an  excessive  degree  of  an 
otherwise  useful  reaction  must  be  combated  by  antipyretics.  More- 
over, various  other  symptoms  present  in  infectious  diseases — above 
all,  the  restlessness,  headache,  anorexia,  etc.,  of  the  febrile  patient — 


THERAPEUTIC  ACTIONS  OF  ANTIPYRETICS          475 

are  favorably  influenced  by  the  calming  action  of  the  antipyretics. 
Consequently,  one  uses  the  antipyretics  more  to  secure  their  sedative 
effects  than  to  lower  the  temperature,  just  as  to-day  one  uses  hydro- 
therapy  in  fever  rather  for  its  favorable  effect  on  the  sensorium  and 
the  circulation  and  respiration  than  for  its  power  of  lowering  tem- 
perature. Consequently,  it  is  the  pharmacological  property  of  the 
antipyretics  of  acting  as  "  fever  narcotics"  which  is  the  chief  factor 
in  their  therapeutic  value.  In  addition  to  this,  we  cannot  deny  that 
in  infectious  fevers  they  may  exert  other  unknown  actions  which 
would  account  for  their  favorable  influence  on  various  symptoms. 

Analgesic  and  Hypnotic  Actions. — The  narcotic  mild  "morphine- 
like"  action  on  the  algesic  centres  comes  into  play  when  they  are 
used  in  the  presence  of  neuralgic  pains  of  different  kinds.  It  is 
possible  that  the  almost  specific  action  of  these  drugs  in  neuralgias  is 
in  part  due  to  an  increased  determination  of  the  blood  to  the 
periphery  of  the  body.  In  headache  their  power  of  relieving  spasm 
of  the  cerebral  arteries  may  play  a  role,  for  Wiechowski  has  found 
that  a  very  large  majority  of  the  analgesics  of  the  group  dilate  the 
cerebral  vessels  as  well  as  the  cutaneous  ones,  and  such  spasmodic 
contraction  of  the  cerebral  vessels  appears  to  occur  in  many  patho- 
logical conditions  in  which  headache  is  a  frequent  symptom, — for 
example,  in  uraemia.  It  is,  therefore,  not  improbable  that  the  aboli- 
tion of  cerebral  vascular  spasm  is  responsible  for  the  relief  of  the  head- 
ache which  often  follows  the  use  of  the  antipyretics  in  such  cases. 

BIBLIOGRAPHY 

Aronsohn  u.  Citron:  Ztschr.  f.  exp.  Path.  u.  Therap.,  1910,  vol.  8. 
Filehne:   Journ.  of  Physiol.,   1894,  vol.   17,  p.   21. 
Finkler:  Pfliiger's  Arch.,  1882,  vol.  29,  p.  235. 
Kast:  Kongr.  f.  inn.  Med.,  1896,  p.  37. 

Krehl :   In  Lubarsch-Ostertag,  Ergebnisse  d.  allg.  Path.,   1896,  vol.   3,  p.  407. 
Krehl:   Pathol.  Physiol.,  Leipzig,  1906,  p.  493. 
Loewy  u.  Richter:   Virchow's  Arch.,  1896,  vol.  145,  p.  49. 
Liidke:   Deut.  Arch.  f.  klin.  Med.,  1909,  vol.  94. 
Naunyn:   Arch.  f.  exp.  Path.  u.  Pharm.,  1884,  vol.  18,  p.  49. 
Pfliiger:  Pfliiger's  Arch.,  1877,  vol.  14,  p.  502. 
Roily  u.  Meltzer:   Deut.  Arch.  f.  Klin.  Med.,  1908,  vol.  94. 
Rovighi:   Prager  med.  Woch.,  1892. 
Unverricht:  Volkmann's  Vortrage,  No.  159. 
Walther:   Zbl.  f.  Bakteriol.,  1891,  p.  178. 

Wiechowski:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48,  p.  376;   1905,  vol.  52, 
p.  389. 

QUININE 

Cinchona  bark  is  obtained  from  different  species  of  cinchona 
which  are  natives  of  the  highlands  of  western  South  America.  Long 
used  by  the  natives  in  malaria  and  other  fevers,  after  the  discovery 
of  South  America  it  was  brought  to  Europe  under  the  name  of 
Jesuit's  powder,  and  became  known  to  the  medical  world  about  the 
end  of  the  17th  century. 

While  formerly  obtained  from  various  wild  varieties  of  the  cin- 


476  PHARMACOLOGY  OF  HEAT  REGULATION 

chona  tree,  it  is  now  chiefly  obtained  from  a  dwarf  variety,  Cinchona 
succirubra,  which  is  cultivated  on  a  large  scale  in  Java  and  the  East 
Indies.  This  bark  contains  more  than  20  alkaloids,  the  so-called 
cinchona  bases,  of  which,  besides  quinine,  only  quinidine,  cinchonine, 
and  chinchonidine  need  be  mentioned.  The  official  bark  must  contain 
5  per  cent,  of  alkaloids. 

While  the  bark  is  still  much  used  in  the  form  of  extracts  and 
tinctures  as  a  bitter  (see  p.  167)  and  tonic  (see  p.  404),  in  the 
treatment  of  fever  it  has  been  entirely  replaced  by  quinine,  first 
prepared  by  Pelletier  and  Caventou  in  1820. 

Quinine,  C20H24N202,  occurs  in  the  bark  in  combination  with 
quinaic  acid  and  quinotannic  acids.  Its  structural  formula  is 
probably  as  follows: 


CH3O 


Of  the  various  water-soluble  and  intensely  bitter  salts,  the 
hydrochloride  is  the  most  useful.  It  is  soluble  in  30  parts  of  water, 
but  the  addition  of  urea,  urethan,  or  antipyrine  renders  it  soluble  in 
equal  parts  of  water.  The  sulphate  is  soluble  in  800  parts  of  water, 
and  the  bisulphate  in  12  parts,  its  solutions  having  an  acid  reaction. 

Various  insoluble  preparations  are  more  or  less  used,  because, 
being  insoluble,  they  are  also  tasteless  or  almost  so.  It  should  be 
remembered,  however,  that  their  insolubility  renders  their  absorption 
slow  and  uncertain.  Of  these  the  more  widely  used  ones  are 

XX 
quinine  tannate,  equinine  (quinine  ethyl  carbonate  ),CO\ 

xOC2oH23 
and  aristochin   (diquinine  carbonic  ester),  CO<  ,   which, 


on  account  of  their    lack    of    taste,   are  frequently  administered  to 
children. 

Quinine  is  unequalled  by  any  other  substance  as  a  specific  for 
malaria,  and  is  also  used  in  the  treatment  of  neuralgia,  whooping- 
cough,  and  other  conditions.  As  an  antipyretic  in  other  infectious 
diseases,  it  possesses  advantages  only  in  those  (typhoid,  septicaemia, 
influenza)  in  which,  with  more  or  less  justification,*  specific  effects  may 
be  attributed  to  it,  or  in  cases  where  its  long-continued  use  is  indi- 
cated in  order  that  its  conservative  action  on  the  proteid  metabolism 
may  be  of  advantage.  These  advantages  are,  however,  counter- 
balanced by  its  weaker  antipyretic  powers  and  by  the  disagreeable 

*  See  footnote,  p.  471. 


QUININE  AND  ANTIPYRINE  GROUP  477 

''side  actions",  of  larger  doses,  particularly  on  the  central  nervous 
system,  even  doses  of  1.0  gm.  at  times  causing  cinchonism,  with  its 
symptoms  of  tinnitus,  deafness,  vertigo,  headache,  and  vomiting.  It 
may  also  act  unfavorably  on  the  alimentary  canal,  the  continued  use 
of  even  small  doses  occasionally  causing  various  types  of  indigestion. 
Skin  eruptions  also  not  infrequently  follow  the  administration  of 
quinine.  Toxic  doses  cause  more  or  less  persistent  deafness  and 
serious  disturbances  of  the  vision,  even  permanent  blindness,  and 
very  large  doses  may  cause  stupor,  coma,  and  collapse  as  a  result  of 
depression  of  the  central  nervous  system  and  of  the  heart. 

While  the  greater  portion  of  quinine  is  combusted  or  otherwise 
decomposed  in  the  organism  (Nishi),  a  portion  is  excreted  unchanged 
by  the  kidneys,  the  urine  acquiring  an  emerald-green  color  on  the 
addition  of  chlorine  water  and  ammonia,  a  reaction  characteristic  of 
quinine  solutions. 

BIBLIOGRAPHY 
JSishi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60,  p.  312. 

ANTIPYRINE  GROUP 

In  the  endeavor  to  obtain  substitutes  for  quinine,  the  start  was 
made  by  searching  for  the  active  nucleus  of  quinine. 

While  quinoline, 

H      H 
C       C 

HC/\/\CH 


N 
H 

one  of  its  decomposition  products,  acts  as  an  antipyretic  and  powerful  narcotic, 
it  so  readily  causes  collapse  that  it  could  not  be  used  in  practice.  However, 
in  1883,  by  the  introduction  of  side  chains  into  quinoline,  the  first  useful 
synthetic  antipyretics,  kairine  and  thallin,  were  obtained;  but  these  also  acted 
too  violently,  for,  although  after  their  administration  the  temperature  falls 
rapidly  with  profuse  sweating,  it  rises  again  after  a  comparatively  short 
time,  this  rise  being  not  infrequently  accompanied  by  a  chill. 

In  1884  Knorr  prepared  and  recognized  the  antipyretic  powers  of 
antipyrine,  a  pyrazolon  derivative,  and  in  1887  the  therapeutic  properties 
of  acetanilide  were  discovered.  While  the  antipyretic  action  of  its  mother 
substance,  aniline,  had  been  recognized  by  Schuchardt  in  1861,  this  discovery  had 
remained  unnoticed.  Although  aniline  itself  is  powerfully  toxic,  the  discovery  of 
acetanilide  indicated  that  among  its  derivatives  and  those  of  the  closely  related 
paramidophenol  there  were  certain  relatively  non-toxic  and  promptly  acting 
antipyretics. 

The  antipyretics  belonging  to  this  pharmacological  group  may, 
from  a  chemical  point  of  view,  be  divided  into  the  aniline  and 
paramidophenol  derivatives  and  the  substances  of  the  pyrazolon 

group. 

BIBLIOGRAPHY 

Schuchardt:  Arch.  d.  Pharm.,  1861. 


478  PHARMACOLOGY  OF  HEAT  REGULATION 

I.  ANILINE  AND  PARAMIDOPHENOL  DERIVATIVES 

Although,  these  mother  substances  are  powerfully  toxic  to  nervous 
cells,  and  although  in  larger  doses  they  cause  the  formation  of 
methasmoglobin,  their  toxieity  may  be  diminished  by  the  introduction 
of  various  side  chains.  Paramidophenol  is  less  toxic  and  more  anti- 
pyretic than  the  ortho-  and  meta-modifications,  which  are  less  power- 
ful antipyretics  and  at  the  same  time  are  more  destructive  to  the 
blood. 

After  large  doses  of  these  substances  the  urine  often  becomes  dark  colored 
and,  on  account  of  the  presence  in  it  of  paramidophenol,  gives  the  indophenol 
reaction — i.e.,  on  the  addition  of  hydrochloric  acid  and  sodium  nitrate  followed 
by  an  alkaline  solution  of  naphthol  and  then  by  NaOH,  acquires  a  red  color, 
which  on  acidification  changes  to  violet. 

O— CSH6 
C 

°C  HC/NCH 


CH3  NH2  \2O.CH5 

Acetanilide.  Paramidophenol.  Phenacetin. 

ACETANILIDE  (antifebrin),  obtained  from  aniline  by  replacing  one 
hydrogen  atom  of  the  amido  group  by  an  acetyl  radical,  occurs  as 
a  crystalline  bitter  substance,  soluble  in  230  parts  of  water.  It  is 
a  prompt  and  powerful  antipyretic  and  analgesic,  of  which  the  dose 
is  0.2  to  0.3  gm.  per  dose.  In  former  times,  as  a  result  of  exceeding 
the  proper  dosage,  numerous  cases  of  poisoning  occurred,  which  were 
characterized  by  cyanosis  of  the  face  and  blueness  of  the  hands  and 
fingernails,  effects  of  the  formation  of  methgemoglobin  and  the  de- 
struction of  the  blood-vessels  (Muller).  In  more  serious  poisoning 
collapse  also  frequently  occurred. 

In  the  body,  the  nucleus  of  acetanilide  undergoes  oxidation,  and 
it  is  excreted  chiefly  in  conjunction  with  sulphuric  and  glycuronic 
acids  as  acetylparamidophenol  (Mutter,  Morncr} . 

PHENACETIN,  acetphenetidin,  is  a  paramidophenol,  in  which  an 
ethyl  radical  has  been  introduced  into  the  hydroxyl  group  and  an 
acetyl  radical  into  the  amido  group,  and  may,  therefore,  be  termed  an 
oxyethylacetanilide.  It  is  a  tasteless  crystalline  powder,  which  is 
very  insoluble  in  water  and  more  active  [?  TR.]  and  less  toxic  than 
acetanilide.  Doses  of  0.25  gm.  produce  some  antipyretic  effects,  while 
after  0.5  to  0.75  gm.  the  antipyretic  effect  is  apparent  after  30 
minutes  and  lasts  for  6  to  8  hours,  usually  unaccompanied  by  dis- 
agreeable side  actions.  In  doses  of  0.3  to  0.7  gm.  it  is  a  useful 
analgesic  and  sedative.  After  larger  doses,  such  as  1.0  gm.  per  dose 
or  3.0  gm.  per  diem,  cyanosis  similar  to  that  caused  by  acetanilide 
has  been  observed,  but  it  rarely  or  never  causes  severe  collapse. 


ANTIPYRINE  GROUP  479 

Lactophenine,  lactyl-para-phenetidin,  is  a  phenacetin  in  which  the  acetyl 
radical  lias  been  replaced  by  the  lactic  acid  radical.  It  is  more  soluble  than 
phenacetin  and  has  proven  a  useful  antipyretic,  possessing  also  considerable 
sedative  powers.  The  maximum  dose  is  0.5  gm.  per  dose,  3.0  gm.  per  diem. 

BIBLIOGRAPHY 

Jaffe  u.  Hilbert:   Ztschr.  f.  physiol.  Chemie,  1888,  vol.  12,  p.  295. 
Morner:   Ztschr.  f.  physiol.  Chemie,  vol.  13,  p.  12. 
Miiller,  Fr.:  Deut.  med.  Woch.,  1887,  No.  2. 

II.  PYRAZOLON  DERIVATIVES 

ANTIPYRINE,  phenyldimethylpyrazolon,  is  a  derivative  of  pyra- 
zolon,  its  constitution  being  illustrated  by  the  following  formula: 

HC CH  H2C CH  (CH3)2C CH 

HclJcH  o=cl    IN  o-cl    JN 

Pyrrol:  N  Pyrazolon:     N  Antipyrine:     N 

I  H  I 

H  C6H8 

It  is  a  colorless  crystalline  powder,  with  a  neutral  reaction  and  a  very 
slightly  bitter  taste,  which  is  soluble  in  equal  parts  of  water.  With  ferric 
chloride  it  gives,  even  in  very  dilute  solutions,  a  blood-red  color,  and  with 
sodium  nitrite  an  intense  green  color,  due  to  the  formation  of  nitroso-antipyrine. 
Following  its  administration,  the  urine  is  usually  dark  colored  and  acquires  a 
reddish-purple  color  on  the  addition  of  ferric  chloride.  A  portion  is  excreted 
unchanged,  but  the  greater  portion  is  excreted  in  conjugation  with  glycuronie 
acid  as  oxyantipyrine. 

In  doses  of  0.4  to  0.8  gm.  antipyrine  is  a  certainly  acting  but 
rather  mild  antipyretic,  the  temperature  usually  falling  during  the 
course  of  3  to  4  hours,  accompanied  by  sweating,  and  rising  again 
gradually.  Alarming  collapse,  such  as  results  from  some  of  the  more 
violently  acting  antipyretics,  is  observed  after  antipyrine  no  more 
frequently  than  with  phenacetin.  It  is  also  very  much  used  as  a 
sedative  and  analgesic,  the  maximal  dose  being  1.0  gm.  per  dose  and 
3.0  gm.  per  diem. 

Although  even  doses  of  2.0  gm.  very  seldom  cause  any  disagreeable 
effects,  still  certain  individuals  exhibit  a  striking  idiosyncrasy  to  an- 
tipyrine. The  most  common  undesirable  effect  is  the  occurrence  of 
skin  eruptions,  which,  while  disagreeable,  are  not  dangerous.  It  is 
only  in  the  presence  of  idiosyncrasy  that  severer  cutaneous  manifesta- 
tions occur,  such  as  inflammatory  swelling  of  the  skin  of  the  face 
and  of  the  genital  organs,  as  also  symptoms  of  irritation  of  the 
mucous  membranes,  such  as  conjunctivitis,  pharyngitis,  laryngitis, 
etc.,  and  occasionally  pronounced  disturbances  of  the  stomach  (Falk). 

Migrainine  is  not  a  chemical  substance,  but  a  mixture  of  antipyrine  85 
parts,  caffeine  9  parts,  and  citric  acid  6  parts. 

Salipyrine,  phenyldimethylpyrazolon  salicylate,  is  a  coarse  crystalline  powder, 
soluble  with  difficulty  in  water,  of  which  the  dose  is  0.5  to  1.0  gm. 


480  PHARMACOLOGY  OF  HEAT  REGULATION 

PYRAMIDON,  dimethylamido  antipyrine,  is  a  crystalline  powder, 
only  slightly  soluble  in  water  and  almost  tasteless.  Its  actions  are 
similar  to  those  of  antipyrine,  but  it  is  3  or  4  times  as  powerful 
[  ?  TR.]  ,  so  that  its  dosage  is  correspondingly  smaller  (0.25  to  0.3  gin.) . 
[Pyramidon,  besides  being  an  antipyretic  and  analgesic,  is  apparently 
also  a  fairly  powerful  hypnotic. — TR.]  After  its  administration, 
antipyryl  urea  and  a  red  coloring  substance,  rubazonic  acid,  appear 
in  the  urine  (Jaffe). 

BIBLIOGRAPHY 

Falk:  Therap.  Monatsh.,  1890,  p.  97. 

Jaffe:  Berichte  d.  deut.  chem.  Ges.,  vol.  34,  1901,  p.  2737. 

III.  SALICYLIC  ACID   GROUP 

Although  free  salicylic  acid  is  antiseptic  and  locally  very  irritant, 
sodium  salicylate  lacks  these  properties. 

SODIUM  SALICYLATE,  a  white  hygroscopic  powder,  soluble  in  equal 
parts  of  water,  acts  in  doses  of  0.5  to  1.0  gm.  as  an  antipyretic,  but 
this  action  is  not  so  elective  as  is  the  case  with  the  above-mentioned 
drugs,  and,  if  the  dose  be  too  large,  symptoms  of  excitation  of  certain 
parts  of  the  central  nervous  system  and  disturbances  of  the  digestion 
readily  appear.  As  undesirable  side  effects,  it  may  cause  dyspnoea 
and  symptoms  like  those  of  cinchonism, — viz.,  deafness,  tinnitus, 
vertigo,  headache,  and  confusion, — and,  if  there  be  a  pronounced  fall 
of  temperature,  it  relatively  often  causes  collapse. 

Those  compounds  of  sodium  salicylate,  such  as  salol  (phenyl 
salicylate),  from  which  it  is  gradually  set  free  in  the  intestine,  cause 
these  disagreeable  side  effects  to  a  slighter  degree,  inasmuch  as  less 
salicylic  acid  reaches  the  circulation  at  one  time.  This  is  also  true 
for  aspirin,  acetyl  salicylic  acid  (see  p.  472),  at  present  widely  used 
in  place  of  the  salicylate  of  soda.  The  antipyretic  effects  of  aspirin 
also  appear  to  be  greater  than  those  of  salicylic  acid,  even  doses  of  0.25 
gm.  producing  pronounced  antipyresis  in  typhoid  fever  (Bondi) . 

BIBLIOGRAPHY 
Bondi:  Ztschr.  f.  klin.  Med.,  1911,  vol.  72,  p.  171. 


CHAPTER  XVI 

PHARMACOLOGY  OF  INFLAMMATION 
NATURE  OF  INFLAMMATION 

IN  its  biological  significance,  inflammation  may  be  looked  upon  as  a 
reaction  of  damaged  tissues,  by  means  of  which  the  damage  is  limited 
and  such  tissues  as  may  be  destroyed  are  removed  and  replaced. 
The  essential  process  in  this  reaction  is  an  alteration  of  the  function 
of  the  vessel  walls,  affecting  not  only  the  smaller  arterioles  and  veins 
but  also  the  capillaries,  as  a  result  of  which  the  vessels  dilate,  losing 
their  tone  and  becoming  permeable  for  both  the  plasma  and  the  red 
and  white  blood-cells,  so  that  transudation  occurs  (Klemensiewitz) . 

The  first  effect  is  an  active  hyperaemia,  causing  heat  and  red- 
ness, and  the  second  an  increased  transudation  into  the  perivascular 
and  interstitial  lymph-spaces,  causing  oedema  or  swelling.  This 
(Bdema  increases  the  tension  in  the  tissues,  and  consequently  causes 
stasis  of  the  blood  and  stretching  or  twisting  of  the  nerves,  with 
tenderness  and  pain.  Finally,  the  leucocytes  and  to  a  less  extent  the 
erythrocytes  leave  the  inflamed  vessels  in  large  numbers,  which  leads 
to  infiltration  of  the  tissues,  phagocytosis,  and  formation  of  pus,  and 
also  to  cytolysis  by  the  pus-cells,  with  a  resulting  dissolution  and 
regeneration  of  tissues.  For  our  purposes  it  is  not  necessary  to  go 
more  deeply  into  these  complex  processes  of  inflammation;  but  it 
should  be  strongly  emphasized  that  in  general  the  reaction  of  inflam- 
mation is  a  useful  process,  and  one  necessary  for  the  cure  of  the 
patient  and  for  replacement  of  destroyed  tissues,  which,  however,  can 
itself  work  harm  to  the  organism  not  only  by  causing  violent  pain 
but  also  by  causing  temporary  or  permanent  functional  disturbances, 
as,  for  instance,  by  the  formation  of  large  exudates  or  cicatrices  or 
as  a  result  of  destruction  of  important  tissues. 

From  such  consideration  it  is  clear  that  it  will  often  be  extremely 
desirable  to  be  able  to  control  inflammation  either  by  stimulating 
or  moderating  its  activity.  Hence  arises  the  demand  for  agents 
which  stimulate  and  those  which  inhibit  inflammation. 

THE  EXCITATION  OR  STIMULATION  OF  INFLAMMATION 

The  vasomotor  disturbances  which  cause  or  initiate  inflammation 
may  be  induced  indirectly  through  the  vasomotor  nerves,  or  directly 
by  the  action  of  chemical  substances  on  the  vessels  themselves.  That 
inflammatory  vascular  disturbances,  with  all  their  sequelae,  may  re- 
sult from  nervous  influences,  is  proven  by  the  occurrence  of  the 
different  forms  of  herpes  as  the  result  of  pathological  processes  in 
the  spinal  ganglia,  as  also  by  the  occurrence  of  circumscribed  hyper- 
31  481 


482  PHARMACOLOGY  OF  INFLAMMATION 

semia  or  of  vesicles,  bullae,  etc.,  as  a  result  of  suggestion  (Heller  u. 
Schultz).  Such  lesions  are  in  all  probability  always  due  to  a  peculiar 
primary  stimulation  of  the  vasodilator  nerves,  which  causes  first  an 
active  hyperaemia  and  later  increased  permeability  of  the  vessels, 
leading  to  transudation,  etc. 

It  is  difficult  to  refrain  from  assuming  in  such  cases  that  certain  trophic 
functions  of  the  vasomotor  nerves,  or  perhaps  specific  trophic  nerves,  which  re- 
spond only  to  certain  adequate  stimuli,  also  play  a  role  in  causing  the  inflam- 
matory reaction,  for  inflammation  never  results  from  simple  vasodilatation,  such 
as  follows  experimental  stimulation  of  vasodilator  nerves  in  the  skin  or  that 
caused  by  the  functional  activity  of  the  organs. 

In*  this  connection  it  is  of  interest  that  these  vasodilator  nerves 
which  accompany  the  spinal  and  some  of  the  cranial  nerves — e.g., 
the  trigeminus — appear  to  be  identical  with  the  sensory  nerves  which 
are  interrupted  in  the  synapses  of  the  spinal  ganglia  (Bayliss).  If 
this  be  actually  so,  the  sensory  nerves  must  transmit  not  only 
centripetal  sensory  impulses  but  also  centrifugal  vasodilator  impulses, 
and,  consequently,  it  must  be  assumed  that  their  peripheral  termina- 
tions are  dichotomous,  one  twig  passing  to  the  cutaneous  sensory 
corpuscles  and  the  other  into  the  smaller  vessels.  One  is  consequently 
tempted  to  assume  the  possibility  of  the  passage  of  stimuli  over  a 
short  path  from  algesic  points  to  the  smaller  vessels,  in  analogy  with 
an  axon  reflex.  This  assumption  would  explain  why  every  painful 
irritation  of  the  skin  causes  almost  immediately  a  local  active  hyper- 
semia,  the  first  stage  of  inflammation,  and  why,  on  the  other  hand, 
when  the  painful  irritation  of  the  skin  is  prevented,  either  by 
analgesic  drugs  or  by  cold,  hyperaemia  does  not  develop  or  is  dimin- 
ished, and  with  it  also-all  other  signs  of  inflammation  (Spiess). 

Bruce's  studies  indicate  that  these  assumptions  are  well  founded,  for  they 
show  that,  when  inflammation  is  due  to  cutaneous  irritation,  it  occurs  even 
after  section  of  the  peripheral  nerve-trunks,  indicating  that  the  reflex  occurs 
independently  of  the  central  nervous  system.  Moreover,  if  the  sensory  nerve- 
endings  be  paralyzed  by  cocaine,  alypin,  or  similarly  acting  drugs,  irritation, 
which  ordinarily  causes  inflammation,  such  as  that  caused  by  cantharidin  when 
applied  to  the  conjunctiva  of  a  rabbit,  produces  no  inflammatory  reaction  so 
long  as  the  anaesthesia  lasts,  or  none  at  all  if  the  sensory  nerve-endings  have 
degenerated,  as  occurs  within  about  eight  days  after  section  of  the  correspond- 
ing sensory  nerves. 

Consequently,  drugs  or  other  agents  which  when  locally  applied 
first  cause  more  or  less  severe  pain  and  resulting  redness  and  inflam- 
mation are  to  be  grouped  together  as  indirect  irritants.  These  cor- 
respond in  general  to  those  drugs  or  measures  which  are  ordinarily 
termed 

CUTANEOUS    IRRITANTS    OR   RUBEFACIENTS 

and  include  heat  and  numerous  substances,  particularly  such  as  are 
volatile  and  readily  penetrate  the  epidermis.  Among  the  most  im- 
portant are  oil  of  mustard,  turpentine,  chloroform,  acids,  ammonia, 
camphor,  and  iodine.  The  prolonged  action  of  all  these  drugs  and 


EXCITATION  OF  INFLAMMATION  483 

of  heat  also,  or  their  use  in  strong  concentrations,  besides  irritating 
the  sensory  nerve-endings,  can  injure  the  tissues  and  can  either  cause 
inflammatory  vasomotor  changes  or  cause  the  death  of  various  tissue 
cells.  In  such  actions  they  resemble  the  members  of  the  group  of 

SUBSTANCES  WHICH  DIRECTLY  EXCITE  INFLAMMATION 

(a)  Specific  vascular  poisons,  substances  which,  without  causing 
any  destruction  or  necrosis  of  the  tissues,  act  only  on  the  vessels,  per- 
haps also  on  the  lymphatics,  dilating  them  and  rendering  them  abnor- 
mally permeable.  These  are  certain  toxic  substances,  probably  proteid 
in  their  nature,  which  belong  to  the  group  of  the  so-called  toxins. 
Among  these  may  be  mentioned  tuberculin  (Pirquet),  diphtheria 
toxin  (B ing el),  abrin  and  ricin,  the  toxic  substances  of  the  pollen 
of  certain  graminaceae,  the  hay-fever  toxin  (Wolf -Eisner),  snake 
venoms,  cantharidin,  the  toxic  substances  of  the  poison-ivy,  Rhus 
toxicodendron  (Ford,  Pfaff),  and  of  the  primula,  Daphne  mezereum, 
the  toxic  substance  in  the  bee's  sting  (Langer),  and  the  Kalahari 
arrow-poison  (Star eke).  These  substances  all  cause  active  hyper- 
aemia  and  serous  infiltration  of  the  tissues.  Those  which  are  able 
to  penetrate  the  skin  when  applied  to  it  cause  papules  or  vesicles 
containing  leucocytes  and  often  large  numbers  of  red  cells. 

These  substances  possess  the  common  characteristic  that  certain 
individuals  or  species  of  animals  are  entirely  or  relatively  immune 
to  them,  their  action  being  dependent  on  a  specific  disposition  of  the 
individual  or  species,  the  nature  of  which  is  still  almost  entirely 
unknown.  Such  disposition  may  be  either  positive  or  negative,  mani- 
festing itself  as  a  specific  susceptibility  or  a  specific  insusceptibility 
of  the  organism  to  a  certain  poison.  In  many  cases  this  disposition 
is  changeable,  but  in  others  it  is  constant. 

Tuberculin  excites  a  distinct  cutaneous  reaction  only  in  individuals  who 
are  or  who  have  been  infected  with  tuberculosis,  and  a  decidedly  more  pronounced 
reaction  in  the  tubercular  tissues  than  in  the  non-tubercular  ones.  The  same 
holds  good  for  reactions  to  other  toxins  and  heterologous  sera  (v.  Pirquet). 

Cantharidin  also  acts  more  strongly  on  tubercular  lesions  than  on  normal 
tissues.  On  the  other  hand,  the  tissues  of  many  species  of  animals  (hedgehog, 
chicken,  frog)  are  in  a  high  degree  immune  to  it.  Contact  with  poison-ivy 
and  the  primula  obconica  ( Wechselmann )  causes  erythema  and  vesication  only 
in  susceptible  individuals.  Snake  venom,  abrin,  ricin,  and  poison-ivy  are  harm- 
less to  the  skin  of  cold-blooded  animals,  but  on  human  skin  they  are  very 
poisonous,  snake  venom  only  when  the  epithelium  has  been  injured,  but  abrin 
and  ricin  through  the  uninjured  cutis.  However,  in  man  repeated  mild  poison- 
ing with  them  leads  to  an  immunity,  which  probably  is  entirely  distinct  from 
the  natural  immunity  of  the  cold-blooded  animals. 

(&)  Caustic  and  Necrotizing  Agents. — A  very  large  number  of 
substances  possess  in  common  the  power  of  killing  all  living  proto- 
plasm alike.  These  are  either  substances  causing  instantaneous  des- 
truction— as  is  the  case  with  trauma,  glowing  heat,  and  corrosives  of 

kinds,  such  as  concentrated  acids  and  alkalies — or  substances,  such 


484  PHARMACOLOGY  OF  INFLAMMATION 

as  arsenic,  which  cause  necrosis  by  more  delicate  but  nonreversible  and 
therefore  progressive  molecular  actions  which  gradually  cause  the 
death  of  the  tissues. 

Whether  rapid  or  slow,  the  death  of  the  tissue  cells  under  all 
conditions  causes  a  chemical  decomposition  of  protoplasm,  with  a 
resulting  formation  of  decomposition  products,  just  as  occurs  in  the 
fermentative  post-mortem  autolysis  of  organs.  These  decomposition 
products  possess  in  a  high  degree  the  power  of  exciting  inflamma- 
tion,— i.e.,  they  produce  the  essential  vascular  changes  and  chemo- 
tactic  assemblage  of  leucocytes.  Apparently  they  irritate  or  render 
more  irritable  the  algesic  nerves,  and  perhaps  they  also  furnish  a 
stimulus  for  the  growth  of  regenerating  tissues. 

The  augmentation  of  the  susceptibility  to  pain  by  inflammatory  products 
is  especially  strikingly  demonstrated  in  the  visceral  peritoneum,  whose  algesic 
nervous  mechanism  ordinarily  responds  only  to  stimuli  resulting  from  extreme 
distention,  but  which  in  peritonitis  responds  to  every  slightest  mechanical — and 
presumably  also  to  every  chemical — irritation. 

BIBLIOGRAPHY 

Bayliss :  Journ.  of  Physiol.,  1900,  vol.  26,  p.  173. 

Bingel:  Munchn.  med.  Woch.,  1909,  No.  26. 

Bruce,  Alex.  N.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1900,  vol.  63,  p.  424. 

Ellinger:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  58. 

Ford:  Journ.  of  Infect.  Diseases,  Chicago,  1907,  vol.  4,  p.  541. 

Heller  u.   Schultz:     Hypnotiseh  erzeugte  Blasenbildung,   Munchn.  med.   Woch. 

1909,  No.  41. 

Klemensiewitz :  Jena,   1908. 

Langer:  Arch.  f.  expt  Path.  u.  Pharm.,  1897,  vol.  38,  p.  381. 
Langer:  Arch,  intern,  de  Pharmacodyn.,  1899,  vol.  6,  p.  181. 
Pfaff:  Journ.  of  exp.  Med.,  1889. 

V.  Pirquet:  Ergebn.  d.  inn.  Med.,  1908,  vol.  1,  p.  420,  literature. 
v.  Recklinghausen:  Hdb.  d.  allg.  Pathol.,  Stuttgart,  1883,  p.  218. 
Spiess :  Munchn.  med.  Woch.,  1906. 

Starcke:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  428. 
Wechselmann:  Monatsh.  f.  pr.  Dermatol.,   1902,  vol.  35. 
Wolf-Eisner:  Das  Heufieber,  Munchen,   1906. 

CLASSIFICATION 

Substances  and  agents  which  excite  inflammation  may  consequently 
be  divided  into  three  groups,  which,  however,  cannot  be  sharply 
differentiated  from  each  other. 

1.  Painful  cutaneous  irritants,  the  rubefacients. 

2.  Vascular  poisons,  the  vesicants  and  pustulants,  which,  whei 
applied  to  the  skin,  cause  vesication  and  pustulation,  and  when  aj 
plied  to  the  mucous  membranes  cause  hyperaemia,  oedema,  and  form? 
tion  of  pus. 

3.  Cytotoxic  agents,  caustic  and  necrotizing  agents. 

THERAPEUTIC  EMPLOYMENT  AND  MODE  OF  ACTION 
Formerly    these    agents    were    used   locally    as    derivatives    anc 
epispastics,  with  the  idea  that  by  their  action  on  the  surface  a  deej 


COUNTERIRRITANTS  485 

seated  inflammation  could  be  brought  to  the  surface.  At  that  time, 
however,  there  was  no  satisfactory  explanation  or  knowledge  of  the 
manner  in  which  counterirritation  produced  its  beneficial  results. 

To-day  their  mode  of  action  is  no  longer  so  incomprehensible, 
since  Bier  has  shown  that  passive  hyperaemia  of  an  organ — i.e.,  a 
hyperaemia  resulting  from  primary  vasodilation — is  a  condition 
of  essential  moment  for  the  protective  reactions  of  inflammation  and 
also  of  importance  for  the  relief  of  pain.  It  has  also  been  shown 
that  irritation  of  the  skin  causes  hyperaemia  not  only  superficially 
but,  according  to  its  severity,  in  more  or  less  deep-lying  as  well  as 
in  more  or  less  distant  parts,  and  even  in  organs  which  are  in  no  way 
directly  connected  with  the  skin;  for  instance,  in  the  thoracic  and 
abdominal  viscera  and  in  the  dura,  in  which  latter  cases  it  is  evident 
that  the  hypenemia  must  be  reflexly  induced.  Head  has  shown  that 
inflammation  of  the  different  viscera  often  causes  a  hypergesthesia 
or  hyperalgesia  of  those  portions  of  the  skin  which  are  innervated 
from  the  same  segments  of  the  cord  to  which  the  sensory  nerves 
of  the  viscera  in  question  pass,  and  that  there  is  a  definite  reflex 
sensory  relationship  between  the  viscera  and  the  skin.  It  would, 
therefore,  appear  more  than  probable  that  an  irritation  from  without 
may  produce  effects  on  the  related  viscera  and  cause  a  hyperaemia, 
and,  as  a  matter  of  fact,  it  is  possible  experimentally  to  demonstrate 
that  this  is  the  case. 

It  is  thus  evident  that  the  term  derivative  as  used  in  connection 
with  the  counterirritants  is  a  misnomer,  for  they  do  not  deprive  the 
organs  of  blood,  but,  on  the  contrary,  augment  their  blood  supply,  and 
thus  under  certain  conditions  may  exert  a  favorable  influence  on  the 
process  of  healing  or  repair. 

In  addition,  sensory  irritation,  according  to  its  severity,  reflexly 
stimulates  or  depresses  (inhibits)  the  circulation  and  the  respiration. 
Thus,  the  respiration  is  stimulated  by  mechanical  or  chemical  stimula- 
tion of  the  trifacial  nerve-endings  in  the  nasal  mucosa,  or  by  cold 
douching  of  the  neck  or  breast  and  by  other  similar  procedures  (see 

341).  Very  violent  cutaneous  irritation,  such  as  that  which 
lay  be  produced  by  mustard  or  cantharides,  diminishes  the  respira- 
tory exchange  in  rabbits,  but  thus  far  this  question  has  not  been 
sufficiently  investigated  in  man  (Mayer). 

Mild  cutaneous  irritation  appears  to  produce  an  opposite  effect, 
increasing  both  the  depth  of  respiration  and  the  respiratory  ex- 
change (Rubner,  Winternitz,  Loewy  u.  Muller,  Matthes). 

The  vasoconstrictor  centres  are  stimulated  even  by  weak  sensory 
stimuli,  and  the  vasodilator  and  vagus  centres  by  powerful  ones. 
While  these  reflexes,  although  of  great  importance  both  for  physiology 
md  therapeutics,  cannot  be  discussed  further  in  this  place,  it  should 
be  mentioned  that  they  play  an  important  role  in  physical  therapy, 
particularly  in  hydro-  and  electrotherapy  (Muller}. 


486  PHARMACOLOGY  OF  INFLAMMATION 

BIBLIOGRAPHY 

Bier:   Hyperiimie  als  Heilmittel,  Leipzig,  1906. 

Head:   Die    Sensibilitatsstorungen    d.    Haut    bei    Visceralerkrankungen,    Berlin, 

1898. 

Loewy  u.  Miiller:  Pfliiger's  Arch.,  1904,  vol.  103. 

Matthes:  v.  Noorden's  Handb.  d.  Path.  d.  Stoffwechsels,  1907,  vol.  2. 
Mayer,  L.:  Trav.  Solvay,  1901,  vol.  4,  p.  73. 
Miiller,  O. :  Med.  Klinik,  1909,  No.  15. 
Rubner:  Arch.  f.  Hyg.,  1903,  vol.  46. 
Winternitz:  Habil.-Schrift,  Halle,  1902. 

CUTANEOUS  IRRITANTS  OR  COUNTERIRRITANTS 

Almost  all  volatile  "  lipoid-soluble "  substances  cause  sensory  irri- 
tation and  rubefaction,  for  they  readily  penetrate  through  the  skin 
and  its  fatty  layer  and  into  the  sensory  nerve-endings. 

Carbon  dioxide  in  the  carbonic  acid  baths,  dilute  alcohol  (20-40 
per  cent.),  and  chloroform  (with  an  equal  amount  of  olive  oil)  act 
in  this  fashion. 

Another  widely  used  counterirritant  is  turpentine,  which  is  ob- 
tained by  the  dry  distillation  of  the  resins  of  the  different  coniferae 
and  which  is  an  ingredient  of  many  plasters,  etc.,  used  as  cutaneous 
irritants. 

It  is  a  mixture  of  pinene,  C10H.ie,  with  small  amounts  of  other  terpenes  and 
traces  of  organic  acids.  Rectified  spirit  of  turpentine  is  obtained  by  distilling 
the  crude  product  with  lime. 

When  left  in  contact  with  the  skin  for  a  time,  it  causes  redness  and 
burning  of  the  skin,  while  on  longer  contact  it  penetrates  more  deeply 
and  causes  vesication  and  pustulation.  It  irritates  the  gastric  and 
intestinal  mucosse  but  slightly,  so  that  1.0  gin.  or  more  may  without 
injury  be  taken  several  times  daily.  It  is  readily  absorbed  and  is 
excreted  through  the  kidneys,  in  part  unchanged  and  in  part  as 
terpene  alcohol  in  conjugation  with  glycuronic  acid,  the  urine  acquir- 
ing some  antiseptic  power  and  an  odor  resembling  that  of  violets. 

The  terpenes  and  resinous  acids  of  copaiba,  cubebs,  and  sandal- 
wood  oil  also  render  the  urine  feebly  antiseptic  as  well  as  astringent, 
for  the  resinous  acids  excreted  in  it  precipitate  albumin  (Vieth). 
These  actions  account  for  the  favorable  effect  of  these  drugs  in 
inflammations  and  infections  of  the  lower  portion  of  the  urinary 
tract. 

In  order  to  avoid  irritation  of  the  stomach  and  intestines,  it  is  best  to 
employ  for  this  purpose  the  salicylic  ester  of  the  oil  of  sandal-wood  (santyl)  or 
esters  of  terpene  alcohols,  which  are  non-volatile  and  very  slightly  irritant. 
These  drugs,  however,  during  their  excretion  can  cause  inflammation  of  the  renal 
capillaries,  just  as  they  do  in  the  skin,  dilating  them  and  rendering  them  more 
permeable,  so  that  diuresis  is  augmented,  and  at  times  albuminuria  and  hsema- 
turia  may  result  from  their  administration.  [Probably  only  when  large  doses 
are  taken  or  when  the  kidney  is  already  damaged  are  these  drugs  likely 
to  cause  any  serious  renal  injury,  but  this  action  should  be  borne  in  mind  when 
considering  their  use  in  large  doses  or  in  nephritic  cases. — TE.] 

OIL  OF  JUNIPER. — The  essential  oil  of  Juniperus  sabina,  a  mixture  of  the 
alcohol,  sabinol,  and  of  various  terpenes,  is  extremely  irritant  to  and  often 


COUNTERIRRITANTS  487 

causes  necrosis  of  the  kidney  epithelium,  as  well  as  elsewhere.  Taken  internally 
it  causes  gastro-enteritis,  haematuria,  and  marked  hyperaemia  of  the  pelvic  organs, 
and  even  abortion.  Externally  it  is  employed  as  an  ointment  for  the  gradual 
removal  of  polypoid  growths,  etc.  [It  is  present  in  gin. — TE.] 

A  small  portion  of  the  turpentine  absorbed  (also  of  cubebs, 
copaiba,  and  oil  of  sandal- wood)  is  excreted  through  the  lungs,  and 
may  act  as  a  disinfectant  and  deodorizer  in  purulent  bronchitis  or 
in  gangrene  of  the  lung.  In  addition  turpentine,  particularly  when 
inhaled,  diminishes  the  bronchial  secretions,  and  may  be  consequently 
used  with  advantage  in  certain  cases  of  bronchitis. 

Camphor,  C10H160,  in  alcoholic  or  oily  solution,  may  be  used  as  a 
mild  counterirritant. 

Arnica,  which  is  widely  used  by  the  laity,  contains  arnicine,  a 
substance  which  causes  cutaneous  irritation. 

Acetic  and  formic  acids  in  various  dilutions  may  be  used  for 
similar  purposes,  as  is 

Ammonia,  which  is  an  ingredient  of  various  liniments,  and  which 
is  also  used  in  smelling  salts  as  a  means  of  reflexly  stimulating  the 
respiratory  and  vasomotor  centres. 

When  concentrated  ammonia  is  respired,  it  immediately  causes  burning 
pain,  a  reflex  spasmodic  closure  or  oedema  of  the  glottis,  and  violent  irritation 
with  swelling  and  exudation  in  the  laryngeal  and  tracheal  mucous  membranes. 
Strong  aqueous  solutions,  when  left  in  contact  with  the  skin,  cause  within  15 
minutes  severe  burning,  redness,  and  vesication. 

Dilute  alkalies,  such  as  solutions  of  potash  or  soda  or  alkaline 
soaps,  especially  sapo  mollis>  in  pure  form  or  as  the  tincture,  produce 
the  same  effects.  Aqueous  solutions  of  the  alkaline  carbonates  or  of 
soaps  emulsify  the  cutaneous  fats  and  facilitate  their  removal,  and 
with  prolonged  action  loosen  the  superficial  layers  of  the  skin  and 
reach  the  sensory  nerve-endings,  causing  burning  or  pain. 

The  alkaline  sulphides  are  more  powerfully  irritant,  for  they 
soften  and  dissolve  the  keratin  of  the  epidermis  and  consequently 
readily  penetrate  it.  Sulphur  itself,  when  applied  in  salves  or  pastes, 
exerts  similar  but  much  weaker  actions,  for  in  contact  with  the  skin 
it  is  gradually  transformed  into  alkaline  sulphides  (p.  209).  "When 
a  paste  of  calcium  sulphide,  prepared  by  the  action  of  H2S  on  milk 
of  lime,  is  rubbed  on  a  hairy  part,  it  acts  as  a  powerful  depilating 
agent,  and  is  actually  used  in  the  Orient  as  a  substitute  for  the  razor. 

Substances  insoluble  in  the  lipoids,  such  as  most  of  the  indifferent 
salts,  do  not  penetrate  the  skin  in  appreciable  amounts  unless  they 
penetrate  into  the  sebaceous  glands,*  where  they  may  be  absorbed 
by  the  living  epithelial  cells,  or  unless  the  skin  has  been  rendered 
more  permeable  by  prolonged  warm  baths  or  poultices.  Previous  re- 
moval of  the  cutaneous  fat,  by  ether,  alcohol,  or  chloroform,  facilitates 
the  absorption  of  such  salts  (Winternitz) . 

*  Such  substances  are  consequently  not  absorbed  when  applied  as  ointments 
unless  they  are  driven  into  the  skin  by  prolonged  and  vigorous  friction. 


488  PHARMACOLOGY  OP  INFLAMMATION 

SALT  BATHS  AND  SEA  BATHS. — None  of  the  constituents  of  such 
baths  are  directly  absorbed  by  the  skin,  except  in  so  far  as  a  certain 
amount  remains  on  the  skin  and,  as  a  result  of  friction,  is  gradually 
driven  into  the  glands  and  between  the  epithelium.  During  this  pro- 
cess they  cause  a  mild  but  often  very  lasting  stimulation  of  the  skin, 
with  a  resulting  redness  and  feeling  of  warmth,  effects  which  may 
reflexly  produce  a  stimulation  of  the  nervous  system  and  metabolism. 

IODINE  is  a  very  efficient  counterirritant  and  one  especially  adapted 
to  cause  sharply  limited  or  readily  modified  counterirritation.  For 
this  purpose  it  is  employed  in  the  form  of  its  tincture  (7  per  cent. 
in  alcohol)  or  as  Lugol's  solution  (5  per  cent.  I,  10  per  cent.  KI  in 
water) . 

As  iodine  is  volatile  at  ordinary  temperature,  it  does  not  long 
remain  on  the  exposed  surface  of  the  skin,  so  that  its  deep  brown 
stains  quickly  fade  to  a  light  yellow.  Its  local  application  is  followed 
by  a  feeling  of  warmth  and  prickling  and  by  a  hyperasmia  of  the 
skin.  Prolonged  or  frequently  repeated  application  may  cause  the 
development  of  large  blisters.  The  hyperasmia  and  serous  infiltration 
caused  by  it  may  extend  quite  deeply  into  the  tissues  and  result  in 
a  cytolytic  dissolution  and  absorption  of  diseased  tissues  or  of  patho- 
genic material.  Iodine  is  consequently  a  favorite  agent  for  the  treat- 
ment of  inflammatory  tumors,  swollen  glands,  arthritis,  etc.  Solutions 
of  iodine  may  also  be  injected  into  cysts,  hydroceles,  etc.,  after  they 
have  been  emptied,  to  cause  inflammatory  reactions  leading  to  ob- 
literation of  such  cavities.  If,  however,  too  large  amounts  are  thus 
injected,  serous  poisoning  may  result  from  the  iodine  which  is  ab- 
sorbed, and  which  is  eliminated  by  the  alimentary  mucosa  and  by  the 
kidneys,  causing  violent  gastro-enteritis  with  persistent  vomiting, 
serous  exudates  into  the  pleural  cavity,  nephritis,  and  profound  coma 
(Rose). 

Solutions  of  iodine  act  much  more  powerfully  on  mucous  mem- 
branes than  on  the  skin,  and  cause  destruction  of  the  superficial 
layers  and  intense  hyperagmia  of  their  lower  layers.  As  the  sensory 
nerve-endings  in  the  mucosa  are  benumbed  or  killed,  the  points  of 
application  remain  for  some  time  benumbed  and  almost  insensitive. 

OIL  OP  MUSTARD  is  also  a  member  of  this  group  of  cutaneous 
irritants. 

It  is  formed  by  the  action  of  a  ferment  on  potassium  myronate  (sinigrin), 
CjoHttNSjjKOa,  which  is  contained  in  the  seeds  of  Brassica  nigra,  and  which  is 
decomposed  hydrolytically  into  the  oil  of  mustard,  isosulphocyanallyl,  CSNC3HC, 
dextrose,  and  potassium  bisulphate.  This  ferment,  myrosin,  is  contained  in  the 
mustard  seeds  and  becomes  active  when  the  pulverized  seeds  are  moistened  with 
water.  [As  this  ferment  is  destroyed  by  heat,  care  should  be  taken  when  making 
poultices  that  the  water  be  not  too  hot,  otherwise  the  ferment  is  destroyed  and 
as  a  consequence  the  mustard's  activity  is  more  or  less  completely  destroyed. — 
TB.] 

This  oil  has  an  extremely  irritant  odor,  and  when  applied  to  the 
skin  causes  burning  and  redness,  and,  if  sufficiently  concentrated  or 


VESICANTS  AND  SUPPURANTS  489 

if  the  action  be  prolonged,  causes  vesication.  It  is  used  as  a  cutaneous 
irritant  either  in  the  form  of  a  mustard  plaster  or  leaf,  in  which 
form,  its  action  develops  gradually,  producing  a  gradually  increasing 
irritating  effect,  or  as  a  liniment  in  the  form  of  a  tincture  or  spirit 
of  mustard,  in  the  strength  of  2  parts  to  100. 

Care  should  be  taken  not  to  permit  it  to  cause  more  than  pro- 
nounced redness  of  the  skin,  for  experience  has  shown  that  the 
blisters  caused  by  it  heal  very  slowly.  The  simultaneous  application 
of  preparations  containing  ammonia  has  also  to  be  avoided,  for 
ammonia  and  mustard  oil  readily  combine  to  form  thiosinamine  with 
the  formula 


CS-NC3H6+NH3 


/NH 
=CS<^ 

\NH2 


FIBROLYSIN.  —  THIOSINAMINE,  or  allyl  sulphocarbamide,  when  combined  with 
sodium  salicylate  is  known  as  fibrolysin.  When  applied  to  the  skin  it  produces 
no  effects,  but  when  injected  subcutaneously  —  thiosinamine  best  in  15  per  cent. 
alcoholic  solution,  fibrolysin  best  in  an  aqueous  one  —  it  causes  severe  pain  and 
hyperaenaia,  and  after  absorption  causes,  it  is  claimed,  a  thus  far  unexplained 
softening  and  absorption  of  the  connective  tissue  of  scars  and  other  connective- 
tissue  growths.  It  has  consequently  been  recommended  as  a  means  of  bringing 
about  the  softening  of  cicatricial  contractures  in  the  extremities  and  of  strictures, 
—  for  example,  strictures  of  the  oesophagus.  Teleky  states  that  under  its  influence 
fresh  adhesions,  such  as  those  following  laparotomies,  fistula  operations,  etc., 
readily  loosen  up,  an  effect  which  may  be  distinctly  undesirable. 

BIBLIOGRAPHY 

Rose:  Virchow's  Arch.,  1866,  vol.  35. 

Teleky:  Ztrbl.  f.  d.  Gr.  d.  Med.  u.  Chir.,  1901,  vol.  4,  literature. 

Vieth:  Med.  Klin.,  1905,  No.  50. 

Winternitz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  28. 

VESICANTS  AND  SUPPURANTS 

Of  the  various  substances  which  may  cause  vesication,  only  three 
are  actually  used  in  medicine,  the  Spanish  fly  or  cantharis,  Daphne 
mezereum,  and  the  fruit  of  Anacardium  occidentale. 

Cantharides.  —  Although  their  common  name  is  Spanish  flies,  these 
are  neither  Spanish  nor  are  they  flies,  but  beetles,  from  2  to  3  cm. 
long,  of  an  emerald-green  color,  which  are  distributed  throughout 
both  hemispheres  in  the  tropical  and  temperate  zones.  Their  bodies 
contain  an  acid  lactone,  cantharidin,  which  is  insoluble  in  water, 
but  readily  soluble  in  fats,  ether,  and  alcohol,  and  to  which  they  owe 
their  activity.  A  number  of  other  allied  species  also  contain  can- 
tharidin. 

Cantharidin  is  applied  to  the  skin  in  the  form  of  a  plaster,  oint- 
ment, or  collodion,  either  to  cause  a  local  reddening  or  hypersemia 
or  to  cause  vesication.  Its  application  is  quite  quickly  followed  by 
a  reddening  of  the  skin  and  pain,  and  after  some  hours  the  epidermis 
is  raised  from  the  corium  and  a  blister  containing  serum  and  many 
leucocytes  is  formed,  by  which  time  the  pain  and  the  redness  have 


490  PHARMACOLOGY  OF  INFLAMMATION 

disappeared  and  the  corium  has  become  pale.  When  the  blister  is 
emptied,  the  epidermis  reforms  rapidly,  as  a  rule,  and  the  blister 
heals  promptly,  but,  if  cantharidin  be  again  applied  to  the  exposed 
corium,  violent  purulent  inflammation  may  result. 

When  swallowed  in  small  amounts,  such  as  0.5  c.c.  of  the  tincture, 
it  causes  only  a  feeling  of  warmth  in  the  epigastrium ;  but  large  doses 
may  cause  violent  gastro-enteritis,  swelling  of  the  submaxillary 
glands,  and  active  salivary  secretion  and  nephritis.  When  very  small 
doses  are  repeatedly  administered  or  when  small  quantities  of  can- 
tharidin are  repeatedly  applied  to  the  skin,  as  a  result  of  the  absorp- 
tion of  the  cantharidin  a  severe  glomemlo-nephritis,  and,  under  some 
conditions,  a  violent  irritation  of  the  urogenital  tract,  with  frequent 
painful  micturition  and  hyperagmia  and  sensory  irritation  of  the 
genital  organs,  may  occur.  These  last  effects  account  for  the  formerly 
not  infrequent  abuse  of  cantharides  as  an  abortificient  and  as  an 
aphrodisiac. 

The  kidney  lesions  appear  to  be  dependent  on  the  reaction  of  the  urine, 
for,  according  to  Ellinger,  cantharidin  causes  only  a  slight  albuminuria  in  rabbits 
as  long  as  the  urine  is  alkaline,  but,  if  this  becomes  acid,  causes  a  very  violent 
hemorrhagic  nephritis,  which  may  prove  fatal.  Consequently,  with  threatened 
cantharidin  poisoning  in  man  the  administration  of  alkalies  would  appear 
to  be  indicated. 

Cantharidin,  being  a  lactone,  combines  in  the  presence  of  water  with  alka- 
lies, forming  soluble  salts.  Sodium  cantharidinate  has  been  employed,  on  Lieb- 
reich's  recommendation,  in  the  presence  of  already  existent  inflammation,  to 
increase  the  permeability  of  the  smaller  blood-vessels,  with  the  idea  of  causing 
more  pronounced  serous  infiltration  with  its  often  curative  effects.  When  thus 
employed,  it  is  administered  subcutaneously  in  very  dilute  solution  (1:  10,000), 
and,  while  curative  effects  have  been  obtained  by  its  use  in  such  conditions  as 
lupus,  such  administration  has  often  caused  renal  irritation,  so  that  its  use  has 
been  abandoned. 

The  dried  bark  of  Daphne  mezereum  has  been  employed  as  a 
household  remedy  as  a  vesicant  and  suppurant.  Cardol,  a  very  irri- 
tant oil  obtained  from  husks  of  Anacardium  occidentale  (cashew- 
nut)  ,  was  also  formerly  employed  as  a  vesicant. 

Almost  all  of  the  other  vesicants  and  suppurants  mentioned  in  the 
introduction  do  not  penetrate  the  intact  epidermis,  but  produce  their 
harmful  effects  on  the  vessels  only  when  applied  to  open  wounds  or  to 
mucous  membranes,  or  when  absorbed  from  subcutaneous  tissues  or 
from  the  alimentary  canal. 

Abrin  and  tuberculin  are  the  only  ones  of  them  which  are  at 
present  of  practical  importance.  The  former  is  a  toxic  substance, 
probably  of  proteid  nature,  contained  in  the  seeds  of  Abrus  prseca- 
torius,  which  when  applied  to  mucous  membranes  causes  a  more  or 
less  violent  purulent  inflammation,  and  which  is  at  times  employed 
in  ophthalmological  practice  (see  p.  160).  Concerning  tuberculin 
the  reader  is  referred  to  page  545. 

BIBLIOGRAPHY 

Ellinger:   Munchn.  med.  Woch.,  1905,  No.  8. 
Liebreich:   Therap.  Monatsh.,   vol.   5,   p.   169. 


ESCHAROTICS  OR  CAUSTICS  491 


IESCHAROTICS  OR  CAUSTICS 
These  are  used  not  to  cause  a  healing  inflammation,  but  to  destroy 
pathological  tissues.  Such  destruction  is  produced  instantaneously 
by  the  action  of  such  powerful  chemical  substances  as  the  caustic 
alkalies,  concentrated  acids,  and  certain  of  the  salts  of  the  heavy 
metals. 

THE  CAUSTIC  ALKALIES,  fused  caustic  potash,  etc.,  dissolve  proteid 
and  keratin,  with  the  formation  of  a  viscid  water-soluble  mass, 
through  which  the  caustic  penetrates  further,  so  that  its  painful 
caustic  action  is-  not  sharply  limited.  By  the  addition  of  the  less 
soluble  lime,  it  is  possible  to  limit  somewhat  the  depth  and  extent 
of  this  caustic  action. 

ACIDS. — Lactic  acid  also  dissolves  proteid  and  keratin,  and  con- 
sequently its  caustic  action  is  not  sharply  limited  and  is  rather 
persistingly  painful.  However,  as  healthy  cells  are  relatively  resist- 
ant to  it,  it  may  be  employed  to  eleetively  destroy  pathological 
tissues. 

Of  the  other  acids,  fuming  nitric  acid  and  trichloracetic  acid  are 
the  ones  most  used  as  caustics,  as  both  of  these  form  from  the  de- 
stroyed tissues  a  firm  leathery  eschar.  It  is  possible  to  produce  with 
them  a  cauterization  which  is  sharply  limited  and  accompanied  by 
pain  of  but  short  duration.  The  eschar  caused  by  nitric  acid  has  a 
lemon-yellow  color,  due  to  the  nitrified  proteid  (xanthoprotein) ; 
that  produced  by  concentrated  aqueous  solutions  of  trichloracetic 
acid  is  white. 

Chromic  acid,  CrO3,  which  occurs  as  red  crystals  readily  soluble 
in  water,  is  a  very  powerful  caustic,  formerly  much  used,  but  now 
abandoned  because  too  poisonous. 

METALLIC  SALTS. — Those  salts  of  the  heavy  metals  which  are  hydro- 
lytically  dissociable  act  as  caustics  in  the  same  fashion  as,  although 
more  weakly  than,  the  free  acids,  precipitating  proteid,  with  the 
formation  of-  acid  albuminates  and  metal  albuminates,  and  thus  de- 
stroying all  protoplasm.  They  are  employed  either  in  pure  form  as 
caustic  pencils,  in  concentrated  watery  solution,  or  in  the  form  of 
pastes. 

If  all  the  constituents  of  the  protoplasm  are  not  equally  affected 
chemically  by  a  substance,  but  if  only  certain  of  them  are  thus  acted 
upon,  the  cell  is  not  necessarily  destroyed,  but  only  damaged  and, 
in  certain  cases,  gradually  killed.  Thus,  for  example,  the  mere  dis- 
turbance of  the  osmotic  condition  of  a  cell  may  bring  about  its  death 
and  decomposition,  particularly  if  its  vitality  is  already  depressed. 
In  such  fashion  pure  water,  by  diminishing  the  osmotic  tension  of 
the  superficial  cells  of  the  gastric  mucosa,  may  kill  them  and  thus 
favor  the  regeneration  of  new  cells,  while  concentrated  salt  solutions, 
pure  glycerin,  etc.,  may  produce  similar  result  by  augmenting  their 
osmotic  tension. 


492  PHARMACOLOGY  OF  INFLAMMATION 

Arsenic,  in  the  form  of  arsenic  trioxide,  a  white  tasteless  powder, 
soluble  with  difficulty  in  water,  is  a  most  certain  means  of  bringing 
about  the  gradual  death  of  cells.  When  applied  to  wounds  or  mucous 
membranes,  it  does  not  directly  cause  a  sensory  or  inflammatory  irrita- 
tion, but  those  cells  which  have  come  in  contact  with  arsenic  in 
solution  gradually  die  and  after  some  days  undergo  necrotic  decom- 
position. In  this  fashion  it  may  cause  destruction  of  tissues  to  a  con- 
siderable depth.  It  is  employed  with  good  results  in  dentistry  as  a 
means  of  killing  and  destroying  the  nerves  in  decayed  teeth  and 
their  roots. 

Antimony  oxide  also  causes  cell  necrosis  in  quite  the  same  fashion. 
The  most  important  antimonial  compound  is  tartar  emetic,  in  which, 
however,  the  antimony  does  not  exist  as  a  free  ion  Sb"',  but  as  the 
ion  SbO'  which  apparently  has  no  direct  toxic  actions.  This  salt  is 
decomposed  by  acids,  with  the  formation  of  the  acid  Sb(OH3),  or  the 
oxide  Sb203,  both  of  which  are  directly  active.  Consequently,  salves 
or  pastes  containing  tartar  emetic,  when  applied  to  the  skin,  cause 
necrosis  only  in  those  places  where  it  is  decomposed  by  an  acid 
secretion  and  changed  into  an  active  form, — i.e.,  only  in  the  mouths 
and  the  follicles  of  the  cutaneous  glands,  in  which  small  areas  of 
necrosis  are  produced,  forming  pustules  resembling  those  of  variola. 

ENZYMES. — Certain  digestive  enzymes,  such  as  trypsin  and  papain, 
a  proteolytic  ferment  obtained  from  Carica  papaya,  have  also  been 
used  to  bring  about  a  gradual  destruction  of  pathological  tissues. 

THE  INHIBITION  OF  INFLAMMATION 

Inasmuch  as  inflammation  is  reflexly  excited,  or  at  least  markedly 
augmented,  by  sensory  stimuli,  it  follows  that  inflammation  will  be 
more  or  less  inhibited  by  all  agents  which  diminish  or  prevent  sensory 
stimulation  at  the  seat  of  inflammation.  Further,  all  agents  which 
prevent  the  abnormal  dilatation  and  permeability  of  the  vessels,  and 
all  which  diminish  the  motility  of  the  leucocytes,  will  also  tend  to 
prevent  or  lessen  inflammatory  reactions;  and,  lastly,  inflammatory 
processes  may  be  etiotropically  combated  by  removing  or  rendering 
harmless  the  pathogenic  agents  causing  the  inflammation. 

In  accordance  with  the  above,  antiphlogistic  agents,  or  agents  re- 
straining inflammation,  may  be  grouped  under  the  three  heads  of 
analgesic,  astringent,  and  etiotropic  agents.  The  last  of  these  will 
be  discussed  in  another  chapter. 

1.  ANALGESIC  ANTIPHLOGISTIC  AGENTS 

One  of  the  most  frequently  used  of  these  is  cold,  obtained  by  the 

local  application  of  ice-bladders,  etc.    It  goes  without  saying  that  the 

effect  of  cold  in  slowing  the  circulation,  paralyzing  the  leucocytes, 

and  constricting  the  vessels  aids  in  controlling  the  inflammation. 

Spiess  in  particular  has  called  attention  to  the  use  of  analgesics  in 


INHIBITION  OF  INFLAMMATION  493 

itrolling  inflammation.  As  emphasized  by  Bruce,  agents  used  for 
this  purpose  should  produce  a  somewhat  lasting  local  analgesic  effect, 
and  should  consequently  be  such  as  will  not  be  dissolved  and  ab- 
sorbed rapidly,  for  otherwise  they  would  leave  the  place  of  applica- 
tion too  quickly.  Consequently,  only  rather  insoluble  ones,  such  as 
anaesthesin  (p.  134),  are  adapted  for  this  purpose,  or  they  must 
be  applied  in  large  amounts  in  case  they  are  sufficiently  nontoxic. 
An  example  of  the  latter  type  would  be  alcohol,  with  which  a  dressing 
for  a  paronychia  is  saturated.  In  the  case  of  the  much-used  chemically 
indifferent  protective  agents,  such  as  gum  arabic,  starch  paste,  in- 
different salves,  plasters,  and  dusting  powders,  the  favorable  effects 
on  the  inflammation  are  undoubtedly  chiefly  due  to  their  power  of 
shielding  the  parts  from  chemical  or  mechanical  sensory  irritation. 

BIBLIOGRAPHY 

Bruce:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  424. 
Spiess:   Munchn.  med.  Woch.,  1906. 

2.  ASTRINGENTS 

As  has  already  been  stated  (pp.  212,  213),  astringents  form  a 
more  or  less  firm  and  impenetrable  coating  on  the  surfaces  of  wounds 
of  mucous  membranes  by  coagulating  the  superficial  layers  of  cells, 
so  that  the  glands  and  lymph-spaces  are  partially  blocked,  while  the 
gland-cells  themselves  are  altered  and  their  secretions  checked 
(Schiitz)  so  that  the  parts  become  dry.  They  also  become  pale  and 
constricted,  because  the  smaller  vessels  are  constricted  and  their 
walls  rendered  less  permeable,  and,  consequently,  the  serous  infiltra- 
tion of  the  tissues  and  the  emigration  of  the  blood-cells  is  lessened 
or  entirely  prevented  (Heinz). 

Moreover,  it  must  not  be  forgotten  that  the  astringents  also  exert 
some  etiotropic  actions,  as  they  act  on  the  exciters  of  inflammation, 
killing  pathogenic  microbes,  and,  what  is  probably  even  more  im- 
portant, precipitating  or  destroying  the  inflammatory  cytolytic  fer- 
ments and  those  substances  which  are  formed  during  every  cell 
necrosis  and  which  have  the  power  of  exciting  inflammation.  With 
the  removal  of  these  phlogogenetic  substances,  the  irritation  of  the 
sensory  nerve-endings  and  the  pain  both  decrease,  so  that  in  this 
fashion  the  astringent  may  also  relieve  pain.  In  this  particular  the 
astringents  show  a  certain  resemblance  to  the  etiotropic  antiseptics, 
which  will  be  discussed  in  a  later  chapter. 

The  chief  members  of  this  group  are  the  various  tannins,  some  of 
the  salts  of  the  heavy  metals  and  of  aluminum,'1  fl'Mrt  to 


It  is  hardly  necessary  to  state  that  numerous  organic  substances,  such  as 
picric  acid,  which  precipitate  and  harden  proteid,  produce  an  astringent  effect, 
T>ut,  on  account  of  other  properties,  such  as  toxicity,  volatility,  etc.,  are  practically 
ill  adapted  for  such  employment.  Among  them  mention  may  hereby  be  made  of 
formaldehyde,  which  may  be  used  in  dilute  solution  (1  to  10  per  cent.)  to 
"Tiaraen  fhe'Skm  and  to  prevent  localized  excessive  sweating. 


494  PHARMACOLOGY  OF  INFLAMMATION 

In  a  former  chapter  sufficient  has  already  been  said  about  the 
various  tannins  (page  214  ff.),  and  in  the  same  place  bismuth  sub- 
nitrate  and  subgallate,  the  subacetate  and  acetate  of  lead,  silver 
nitrate,  and  lime  water  have  all  been  discussed. 

All  the  caustics  mentioned  above,  which  form  a  firm  and  tough 
eschar,  when  used  in  high  dilution  act  as  astringents,  so  that,  even  in 
the  case  of  a  cauterization,  such  as  that  produced  by  silver  nitrate, 
the  traces  of  the  caustic  agent  which  penetrate  into  the  underlying 
tissues  act  there  as  astringents.  Consequently  the  curative  effects  of 
many  of  these  substances  depend  on  such  a  combination  of  their 
caustic  and  astringent  actions. 

Of  such  caustics  the  most  important  practically  are  silver  nitrate, 
the  sulphates  and  acetates  of  copper,  alum  and  zinc,  and  the 
lic[uor  ferrj  pesqiiirhlnrqfi  The  latter  is  also  employed  as  a  means  of 
checking  bleeding,  on  account  of  its  power  of  causing  coagulation  of 
the  blood. 

If  such  caustics  do  not  form  solid  compounds  with  the  tissues, 
but,  like  the  salts  of  mercury,  arsenic,  and  antimony,  form  only  soft 
or  water-soluble  products,  they  produce  no  astringent  effects  what- 
ever. On  the  other  hand,  the  caustic  action  is  very  slight  or  entirely 
absent  in  the  case  of  those  substances  which,  on  account  of  their  slight 
solubility  in  water  or  their  slight  power  of  diffusion,  are  able  to  pro- 
duce only  a  weak  and  extremely  superficial  chemical  reaction.  In 
addition  to  the  tannins,  the  following  are  examples  of  such  substances : 
Zinc  oxide,  lead  oxide,  lead  carbonate,  lead  subacetate,  and  the 
subnitrate,  subgallate,  and  subsalicylate  of  bismuth. 

BIBLIOGRAPHY 

Heinz:   Virchow's  Arch.,   1889,  vol.   116. 

Schiitz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27. 

BISMUTH  SALTS. — While  the  subgallate  and  subsalicylate  of  bis- 
muth possess  the  advantage  over  the  subnitrate  that,  when  admin- 
istered internally,  they  cannot  cause  nitrite  poisoning,*  they  are 
inferior  to  it  in  that  neither  gallic  nor  salicylic  acids  are  astringents. 

Although  the  basic  bismuth  salts  are  insoluble  in  water,  and  can- 
not be  absorbed  in  appreciable  amounts  either  by  mucous  membranes 
(even  inflamed  ones)  or  by  granulating  wound  surfaces,  still,  when 
brought  in  contact  with  fresh  wounds,  they  without  exception  are 
transformed  into  soluble  compounds  of  unknown  character,  which 
are  absorbed,  and  consequently  under  these  conditions  they  may 
cause  serious 

Bismuth  Poisoning. — This  very  closely  resembles  subacute 
mercurial  poisoning,  and  is  characterized  by  the  formation  of  dirty, 
dark-colored  ulcerations  in  the  mouth,  particularly  where  the  tongue 
or  the  gums  are  eroded,  and  by  extensive  necrosis  in  the  large  in- 

*  See  p.  216. 


INHIBITION  OF  INFLAMMATION  495 

itine,  and  also  by  glomerulo-nephritis  (Kocher,  Mahne).  The  ulcer- 
ations  in  the  mouth  and  the  large  intestine  result  from  the  intra- 
cellular  and  intravascular  precipitation  of  the  oxide  of  bismuth  by 
hydrogen  sulphide  (H.  Meyer  u.  Steinfeld). 

All  other  bismuth  compounds,  such  as  xeroform  (bismuth  tribro- 
ophenol),  orphol  (bismuth  /8-naphthol),  airol  (bismuth  iodosubgal- 
late),  etc.,  may  produce  toxic  effects,  and  it  is  consequently  entirely 
incorrect  to  state,  as  is  too  often  done,  that  any  bismuth  compound 
is  absolutely  non- toxic. 

BIBLIOGRAPHY 

x>cher:   Volkmann's  Klin.  Vortr.,  1882,  p.  224. 
Mahne:   Berl.  klin.  Woch.,  1905,  No.  42. 

er,  H.,  u.  Steinfeld:   Arch.  f.  exp.  Path.  u.  Pharm.,  1885,  vol.  20. 


ALUMINUM  SALTS. — The  above  is  also  true  for  the  salts  of  alumi- 
na, for  they  too  are  toxic  if  absorbed  (Siem).  Aluminum  subacetate 
and  dilute  solutions  of  alum,  aluminum  sulphate,  alsol  (A.  aceto- 
tartrate),  and  aluminol  (A.  naphtholsulphonate)  are  all  used  as 
astringents. 

BIBLIOGRAPHY 
Siem:  Diss.,  Dorpat,  1886. 

LIME  SALTS. — In  a  former  section  (p.  217)  the  manner  in  which 
lime  water  acts  as  a  local  astringent  has  been  explained,  and  also  its 
superiority,  for  certain  cases,  to  all  other  acid-reacting  or  insoluble 
astringents,  owing  to  its  power  of  dissolving  mucus.  This  property 
is  of  particular  value  in  the  treatment  of  diphtheritic  inflammation 
of  the  throat,  in  which  thick  pseudo-membranes  containing  much 
mucin  are  formed  (Harnack). 

The  neutral-reacting  calcium  chloride,  however,  may  also  in  a 
certain  sense  be  considered  an  astringent,  and  a  remotely  acting  one 
at  that.  In  animals,  in  which  the  total  amount  of  calcium  has  been 
increased  by  the  subcutaneous  injection  of  calcium  chloride,  inflam- 
mation does  not  occur  at  all  or  only  in  a  mitigated  form. 

in  Bucii  animals  the  instillation  of  oil  of  mustard  or  of  abrin  into  the  con- 
junctiva is  not  followed  by  the  usual  pronounced  hyperaemia,  chemosis,  and  pus 
formation,  and  pleural  and  pericardial  effusions  also  fail  to  result  from  certain 
injections  and  poisonings  which  ordinarily  cause  them  (Chiari) ,  while  the 
development  of  exanthemata  is  prevented  or  at  least  rendered  very  difficult 
(Wright,  Luithlen).  It  appears,  therefore,  that  calcium  acts  on  the  smaller 
blood-vessels,  and  perhaps  also  the  lymph-vessels,  so  as  to  render  them  less  per- 
meable to  the  blood  plasma  and  cells. 

These  effects  are  produced  most  certainly  by  subcutaneous  injection 
and  last  about  24  hours,  but  they  may  also  follow  oral  administra- 
tion, although  more  slowly  and  in  slighter  degrees.  In  man  100  c.c. 
of  a  2  per  cent,  solution  of  chloride  of  calcium  may  be  taken  internally 
(Leo),  but  only  dilute  solutions  (1-2  per  cent.)  should  be  administered 
subcutaneously,  as  more  concentrated  ones  cause  necrosis  at  the  point 
of  injection.  It  must  also  be  emphasized  that  calcium  salts  are  by  no 


496  PHARMACOLOGY  OF  INFLAMMATION 

means  non-toxic,  for  animals,  into  which  0.3  to  0.4  gin.  CaCl2  per 
kilo  have  been  injected  subcutaneously,  die  in  a  few  days  as  a  result 
of  a  central  paralysis. 

BIBLIOGRAPHY 

Chiari  u.  Januschke:  Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  65,  p.  120. 

Harnack:  Berl.  klin.  Woch.,  1888,  No.  18. 

Leo:  Deut.  med.  Woch.,  1911,  No.  1,  here  literature. 

Luithlen:  Wien.  klin.  Woch.,  1911,  No.  20. 

Wright,  A.  F.:  Lancet,  1896,  vol.  1,  p.  153;  1905,  vol.  2,  p.  1096. 

EPINEPHRIN  acts  in  a  different  fashion,  but  also  prevents  infla^n- 
mation.  As  is  well  known,  when  subcutaneously  or  intravenously  ad- 
ministered, it  markedly  delays  the  absorption  of  chemical  substances 
from  serous  cavities  and  from  the  subcutaneous  tissues,  probably  on 
account  of  the  persistent  contraction  of  the  blood  and  lymph 
capillaries  (Meltzer,  Exner). 

As  shown  by  recent  experiments  of  Frohlich,  this  vasoconstriction  also  pre- 
vents inflammatory  transudation,  for,  after  the  intravenous  injection  of  the 
more  persistently  acting  and  less  toxic  d-epinephrin,  the  oil  of  mustard  does  nofc 
cause  inflammation  of  the  rabbit's  conjunctiva. 

BIBLIOGRAPHY 

Exner,  A.:  Ztschr.  f.  Heilk.,  1903,  No.  12. 

Frohlich:  Zbl.  f.  Physiol.,  1911,  vol.  25,  No  1. 

Meltzer  u.  Auer:  Proc.  Soc.  exp.  Biol.  and  Med.,  1903-04,  vol.  1,  p.  38. 

QUININE  may  also  in  a  certain  limited  sense  be  considered  a  sub- 
stance possessing  the  power  of  inhibiting  inflammation,  for  it  dimin- 
ishes the  motility  of  leucocytes  and  thus  prevents  their  diapedesis, 
as  proven  by  the  observations  made  by  Binz  on  the  inflamed  mesentery 
of  the  frog.  It  is  consequently  not  impossible  that  threatening  forma- 
tion of  pus  may  be  prevented  by  the  internal  administration  of 
quinine,  or  that  purulent  foci  already  extant  may  be  prevented  from 
spreading  (Binz).*  In  purulent  eatarrhal  inflammations  of  the  upper 
air-passages,  large  doses  of  quinine,  according  to  common  experience, 
exert  an  inhibitory  influence  on  the  inflammation.  This  may  justify 
the  presence  of  quinine  as  a  constituent  of  various  coryza  tablets,  f 

According  to  Winternitz,  ethereal  oils  also,  after  their  absorption 
into  the  blood,  have  the  power  of  limiting  the  formation  of  exudates 
in  inflamed  tissues  and  of  favoring  their  absorption. 

BIBLIOGRAPHY 
Binz:  Virchow's  Arch.,  vol.  46. 
Winternitz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1901,  vol.  46. 

*  Satisfactory  experimental  and  clinical  proof  of  such  action  is,  as  far  as  the 
translator  knows,  still  lacking. 

t  [Inasmuch  as  these  tablets  contain  only  small  amounts  of  quinine  it  is 
probable  that  such  effects  as  they  produce  are  due  entirely  to  the  atropine  which 
almost  all  of  them  contain. — TB.] 


CHAPTER  XVII 
ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

IN  so  far  as  drugs  alter  the  functions  of  the  various  organs  in  the 
body  they  may  be  looked  upon  as  acting  organotropically.  In  con- 
trast to  these  is  a  group  of  drugs  with  which  we  are  able  to  influence 
the  causative  agents  of  disease  without  producing  essential  changes 
in  the  functions  of  the  various  organs,  and  which  may  consequently 
be  called  etiotropic  drugs.  The  causes  of  disease  against  which  they 
direct  their  activity  may  be  animate  or  inanimate, — i,e.,  parasites, 

Icteria,  protozoa,  etc.,  or  poisons,  such  as  the  so-called  toxins. 

Outside  of  the  body  the  destruction  of  bacteria  is  attained  by  the 
use  of  disinfectant  drugs  and  various  physical  agents,  particularly 
heat.  On  the  surface  of  wounds,  mucous  membranes,  etc.,  bacteria 
may  be  combated  by  antiseptics,  while  against  the  animal  parasites 
of  the  alimentary  canal  the  antiparasitics  are  used.  In  such  eases 
etiotropic  drugs  come  in  contact  with  the  pathogenic  organisms  not 
inside  of  the  tissues  but  on  the  surface  of  the  higher  organism,  while 
in  other  cases  it  is  possible  to  destroy  the  disease-producing  organisms 
(protozoa)  in  the  tissues  themselves  without  essentially  disturbing 
the  organic  functions  of  the  body  of  the  host.  This  we  call  specific 
antiseptic  therapy. 

If  poisons  taken  into  the  stomach  are  rendered  harmless  by  the 
proper  antidotes, — for  example,  phosphorus  by  copper  sulphate, 
arsenic  by  calcined  magnesia, — the  antidote  really  acts  on  the  cause 
of  disease  in  a  fashion  analogous  to  the  manner  in  which  an  an- 
thelmintic  acts  on  a  parasite.  In  a  similar  fashion  inanimate  causes 
of  disease,  even  after  penetration  into  the  tissues,  may  be  directly 
attacked  by  antidotal  agents.  Thus,  hydrocyanic  acid  and  various 
cyanide  compounds  may  be  transformed  into  non-toxic  substances  by 
sodium  hyposulphite,  even  after  they  have  been  absorbed  into  the  cir- 
culation. As  these  antidotes  have  already  been  discussed  elsewhere, 
they  will  not  be  considered  in  this  section,  but,  of  the  inanimate  causes 
of  disease,  only  the  toxins,  which  stand  in  the  very  closest  relation- 
ship to  living  pathogenic  agents,  will  be  dealt  with  in  connection  with 
antitoxin  therapy. 

GENERAL  ANTISEPTICS 

In  high  dilutions  antiseptics  do  not  kill  bacteria  but  only  inhibit 
their  growth  and  multiplication,  while  in  somewhat  greater  concen- 
tration they  kill  the  adult  forms  but  not  the  spores,  these  being  de- 
stroyed only  by  strong  solutions  of  the  most  powerful  antiseptics. 

METHODS  OF  INVESTIGATION. — In  order  to  determine  the  power  of  a  substance 
inhibit  bacterial  development, — i.e.,  its  antiseptic  power, — it  is  added  to  the 
32  497 


498  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

fluid  culture-medium  in  varying  amounts,  and  the  lowest  concentration  is  deter- 
mined which  prevents  the  growth  of  the  bacteria  or  the  development  of  the 
spores.  In  investigating  the  disinfectant  value — that  is  to  say,  the  bactericidal 
power — of  a  substance,  silk  threads,  pieces  of  glass,  beads,  and  the  like  are  cov- 
ered with  bacteria  or  spores,  in  so  far  as  it  is  possible  in  equal  numbers,  and  these 
test  objects  are  left  for  different  periods  of  time  in  the  disinfectant  solution, 
which  is  kept  at  a  fixed  temperature.  After  the  disinfectant  has  acted  upon 
these  objects,  the  bacteria  must  be,  as  far  as  possible,  freed  from  it,  in  order 
that  a  portion  of  the  disinfectant  may  not  be  carried  over  into  the  fresh  culture- 
medium,  for,  as  even  very  small  amounts  of  disinfectants  are  sufficient  to  inhibit 
bacterial  growth,  this  might  lead  to  the  false  conclusion  that  the  bacteria  had 
been  killed.  Thus,  for  example,  following  a  suggestion  of  Geppert,  who  was  the 
first  to  call  attention  to  this  source  of  error,  mercurial  compounds  are  rendered 
harmless  by  precipitating  them  with  ammonium  sulphide.  For  further  details 
concerning  the  method  of  determining  disinfecting  powers  the  reader  is  referred 
to  text-books  on  bacteriology. 

As  in  all  living  cells,  in  the  bacterial  cell  also  the  carrier  of  vital 
functions  is  a  mixture  of  colloids  in  a  state  of  ' '  Quellung ' '  or  hydra- 
tion,  principally  proteids  and'  lipoids,  which  latter  are  for  the  most 
part  substances  of  as  yet  unknown  constitution  but  which  resemble  the 
fats  in  their  solubilities.  In  this  mixture  of  a  certain  definite  structure, 
the  protoplasm,  the  ferment  actions  and  the  vital  functions  of  the 
cells,  such  as  assimilation,  growth,  and  reproduction,  take  place  in  an 
aqueous  solution  of  salts,  the  concentration  of  which  is  definite  for 
each  organism  but  varying  within  certain  limits  with  the  varying 
species  of  bacteria.  A  change  of  the  salt  content  of  the  medium  may 
inhibit  the  vital  activity  of  the  bacteria,  and  may,  with  them  as  with 
other  plant  cells,  cause  plasmolysis  (A.  Fischer),  while  drying  renders 
the  life  of  the  bacteria  latent,  but  destroys  it  only  after  very  complete 
removal  of  all  water  or  when  the  drying  has  lasted  for  a  very  long 
time. 

Every  alteration  in  the  chemical  composition  of  the  protoplasm  causes  an 
injury  to  the  bacterial  cells.  An  example  of  the  delicacy  with  which  these  cells 
react  to  alterations  in  the  chemical  composition  of  the  medium  in  which  they 
are  placed,  is  furnished  by  the  anaerobic  micro-organisms,  whose  life  is  so  depend- 
ent on  a  very  low  oxygen  tension  that  an  increase  in  the  amount  of  oxygen  in 
the  surrounding  medium  is  fatal  or  harmful  to  them. 

Most  especially  an  alteration  or  change  affecting  the  colloids  or 
lipoids  results  in  damage  to  the  protoplasm,  and  consequently  every 
foreign  substance  must  act  as  a  poison  to  bacteria  if  it  is  able  to  pene- 
trate into  their  interior  and  enter  into  a  chemical  or  physicochemical 
reaction  with  their  vitally  important  constituents.  Inasmuch  as  these 
constituents  of  the  protoplasm  of  all  animal  and  vegetable  cells  are 
similar,  and  as  the  bacterial  cells  in  respect  to  their  permeability  do 
not  differ  essentially  from  other  cells,  it  follows  that  all  general 
cytotoxins  are  also  general  poisons  for  bacteria. 

While  in  all  its  detail  it  is  not  known  on  which  of  these  reactions  the 
bactericidal  power  of  the  general  antiseptics  depends,  the  disinfect- 
ing power  of  the  salts  of  the  heavy  metals,  of  acids,  and  strong  alka- 
lies is  attributed  to  their  power  of  producing  changes  in  the  proteid 


GENERAL  ANTISEPTICS  499 

constituents  of  the  bacteria,  for  their  bactericidal  power  runs 
parallel  with  their  powrer  of  reacting  with  proteids.  In  connection 
with  the  absorption  of  poisonous  substances  which  possess  affinities 
for  the  lipoids,  their  toxic  action  may  be  attributed  to  a  disturbance 
of  the  relationship  between  the  lipoids  and  the  other  constituents  of 
the  bacterial  cells.  Similarly  the  alteration  of  the  protoplasm  by 
powerful  oxidizing  agents,  which  also  act  as  antiseptics,  is  readily 
understood.  On  the  other  hand,  however,  prussic  acid  poisons  the 
cells  by  inhibiting  oxidation,  probably  by  inhibiting  the  oxidases.  It 
is  thus  seen  that  the  bacterial  cells  may  be  affected  in  many  quite 
different  fashions. 

Inasmuch  as  the  disinfectants  are  also  general  cell  poisons,  the 
most  that  may  be  expected  is  quantitative  differences  between  the 
susceptibility  of  the  bacteria  and  that  of  animal  cells.  These  may 
in  the  first  place  rest  upon  differences  in  permeability. 

The  outer  layer  of  the  protoplasm,  or  the  plasma  skin,  which  in 
vegetable  cells  lies  on  the  inner  side  of  the  cell  membrane,  behaves 
in  many  bacteria  in  a-  manner  not  essentially  different  from  its  be- 
havior in  other  animal  and  vegetable  cells,  being  readily  permeated 
by  water  and  by  many  substances  which  are  soluble  in  lipoids  but 
permeated  with  difficulty  by  salts.  Such  bacterial  cells  consequently 
readily  undergo  plasmolysis.  In  other  varieties,  however,  this  outer 
layer  is  readily  permeable  for  salts  also.  Consequently  the  proto- 
plasm of  bacteria  is,  generally  speaking,  no-  better  protected  from  an 
elective  absorption  by  its  outer  layer  than  is  the  case  with  other  cells. 

The  behavior  of  the  external  cell  membrane  is  of  more  importance.  In  other 
vegetable  cells  this  cellulose  covering  is  readily  permeable  for  all  substances,  and 
consequently,  under  the  influence  of  substances  with  little  power  of  permeation, 
the  differences  in  osmotic  pressure,  which  lead  to  plasmolysis,  occur  only  on  both 
sides  of  the  external  layer  of  the  protoplasm.  The  bacterial  cell  membrane,  how- 
iver,  does  not  consist,  as  in  other  vegetable  cells,  of  pure  cellulose  but  also 
•ntains  nitrogen,  and  consequently  its  permeability  is  not  to  be  taken  for  granted 
being  the  same  as  that  of  other  vegetable  cells.  On  the  contrary,  it  forms  a 
rrier  which  opposes  a  resistance  to  the  entrance  into  the  cell  of  various  sub- 
inces.  This  may  be  observed  in  connection  with  the  action  of  poisons  which 
ter  passing  through  the  cellulose  membrane  produce  alterations  in  the  con- 
tituents  of  the  plasma  skin.  Thus,  for  example,  other  vegetable  cells  are  so 
•apidly  killed  by  */&  normal  (molecular)  NaCl  solution  which  is  saturated  with 
odine  that  plasmolysis  does  not  occur,  for  the  iodine  enters  immediately  into  a 
lemical  reaction  with  the  surface  layer  of  the  protoplasm  and  abolishes  its 
mipermeability  for  the  sodium  chloride.  On  the  other  hand,  one  may  produce 
ilasmolysis  of  bacteria  with  this  very  same  solution  (A.  Fischer),  for  in  them 
,he  iodine  penetrates  more  slowly  through  the  external  membrane  of  the  bacteria. 
Solutions  of  various  metallic  salts  behave  in  a  similar  fashion. 

The  membranes  surrounding  the  spores  protect  the  internal  con- 
tents of  the  cell  much  more  effectively  than  does  the  external  mem- 
brane of  the  bacteria,  and  it  has  been  found  that  neither  concentrated 
sodium  chloride  solution  nor  distilled  water  nor  concentrated  alcohol 
inflicts  any  damage  upon  spores,  and  that  water,  even  after  months, 
penetrates  into  them  with  great  difficulty.  It  is  probable,  therefore, 


500  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

that  the  astonishing  resistance  of  spores  to  the  actions  of  certain 
antiseptics  is  to  be  attributed  to  their  slight  permeability.  Thus,  for 
example,  spores  in  general  are  particularly  resistant  to  the  toxic 
action  of  phenol  and  other  lipoid  soluble  disinfectants  which  readily 
penetrate  into  the  interior  of  adult  bacteria.  For  instance,  anthrax 
spores  are  killed  by  4  per  cent,  carbolic  acid  only  when  exposed  to 
it  for  days,  while  the  adult  bacilli  are  killed  in  2-10  minutes  by  a  1  per 
cent,  solution.  Spores  are  also  far  more  resistant  to  corrosive  subli- 
mate, 0.1  per  cent.  HgCl2  killing  anthrax  bacilli  in  10  minutes  but  the 
spores  only  after  two  hours.  This  tough  skin  of  the  spores  may  con- 
sequently be  considered  as  a  protective  organ  comparable  to  the 
shells  which  cover  most  vegetable  seeds. 

In  addition  to  differences  in  the  permeability  of  bacterial  cells, 
differences  in  their  susceptibility  to  various  antiseptics  is  due  in 
part  to  their  varying  power  of  retaining  and  storing  up  the 
penetrating  substances  in  their  protoplasm.  When  foreign  sub- 
stances pass  through  the  outer  membrane,  as  a  general  thing  they 
continue  to  diffuse  throughout  the  protoplasm  until  an  equilibrium 
has  been  established  on  both  sides  of  the  outer  layer,  but,  if  the 
foreign  substance  undergoes  a  chemical  change  after  absorption  into 
the  interior  of  the  cell,  such  an  equilibrium  cannot  be  established. 
Under  such  conditions  bacterial  cells  may  absorb  considerable  amounts 
of  substances,  even  from  very  dilute  solutions,  and  hold  them  fast 
in  the  form  of  new  compounds.  Thus,  marine  .algae  store  up  iodine  in 
a  form  which  is  non-toxic  to  them,  and  certain  plants  are  similarly 
able  to  absorb  from  soil  containing  considerable  quantities  of  zinc 
as  much  as  13  per  cent,  of  their  weight  in  zinc  salts  (Czapek}.  In 
other  cases,  however,  the  new  compound  may  be  poisonous  for  the 
cell,  so  that  a  gradual  poisoning  results  from  its  accumulation.  The 
best-known  example  of  such  phenomena  is  the  oligodynamic  action 
of  solutions  of  metallic  salts  first  observed  by  Ndgeli  in  algae. 

In  Bokorny's  experiments,  only  water  distilled  from  glass  into  glass  was 
non-toxic  for  the  algae,  while  if  the  water  had  come  into  contact  with  copper, 
silver,  lead,  etc.,  it  was  found  to  be  toxic  to  these  organisms,  although  it  was 
impossible  by  chemical  reagents  to  recognize  the  presence  of  metallic  compounds 
in  this  water,  so  great  was  the  dilution.  That  the  toxic  action  under  these 
conditions  was  due  to  a  gradual  accumulation  of  the  metal  in  the  cells  of  the 
algae,  resulting  from  the  absorption  of  the  metal  from  the  infinitely  dilute  solu- 
tion, is  evidenced  by  the  fact  that  by  first  bringing  large  quantities  of  algae 
into  these  solutions  they  could  be  rendered  non- toxic  for  others  introduced  later. 

Lipoid  Solubility  of  Antiseptics  of  Decisive  Importance. — The 
solubility  of  the  antiseptics  in  the  outer  layer  of  the  protoplasm  is 
the  chief  deciding  factor  for  the  rapidity  with  which  they  penetrate 
into  the  body  of  the  bacteria.  The  power  possessed  by  this  membrane 
of  dissolving  many  substances  closely  resembles  the  same  power  of 
fats,  and,  consequently,  in  general  all  substances  which  dissolve 
readily  in  fats  are  passively  absorbed  into  the  interior  of  these  cells. 


GENERAL  ANTISEPTICS  501 

When  foreign  substances  penetrate  into  the  cells  from  the  tissue 
fluids  of  the  body, — that  is  to  say,  from  an  aqueous  medium, — their 
absorption  will  depend  on  the  partition  coefficient  resulting  from 
their  solubility  on  the  one  side  in  water  and  on  the  other  side  in  fat- 
like  solvents.  In  accordance  with  this  law,  first  promulgated  by 
Overton,  lipoid  soluble  substances  must  necessarily  be  readily  and 
rapidly  absorbed  by  bacteria.  This  fact  gives  to  a  group  of  organic 
antiseptics,  the  phenols,  cresols,  alcohol,  etc.,  certain  advantages  over 
the  inorganic  ones,  of  which  only  a  few,  such  as  corrosive  sublimate, 
iodine,  and  osmic  acid,  are  soluble  in  lipoids. 

On  the  other  hand,  most  of  the  salts,  as  well  as  the  alkalies  and 
inorganic  acids,  in  short  most  solutions  of  strong  electrolytes,  are 
hardly  at  all  soluble  in  fats,  and  consequently  they  are  not  absorbed 
through  the  unaltered  plasma  membrane.  It  is  only  when,  by  virtue 
of  their  power  of  precipitating  or  dissolving  proteid,  they  destroy 
the  external  layers  of  the  bacteria,  that  they  are  able  to  penetrate 
into  the  interior  of  these  cells. 

From  these  points  of  view  a  division  of  the  general  antiseptics 
into  two  groups  may  be  made, — those  which  are  soluble  in  the  lipoids 
and  which  consequently  are  absorbed  into  the  superficial  layers  of  the 
bacteria,  which  contain  more  or  less  lipoids,  forming  one  group, 
while  the  second  group  consists  of  those  which  are  insoluble  in  the 
lipoids  but  which,  by  attacking  the  proteid  constituents  of  the 
bacterial  cells,  are  able  to  penetrate  into  them.  Such  disinfectants 
as  are  soluble  in  the  lipoids  and  at  the  same  time  precipitate  pro- 
teids  belong  to  both  groups. 

The  different  manner  in  which  the  absorption  of  antiseptics  of 
these  two  groups  occurs  is  of  more  or  less  practical  importance.  The 
disinfecting  power  of  the  lipoid  soluble  antiseptics  is  determined 
largely  by  their  partition  coefficient  between  the  cells  and  the  sur- 
rounding media,  and  this  is  the  reason  why,  when  applied  in  oily 
solution,  carbolic  acid  has  no  disinfecting  power  (Koch),  for,  on 
account  of  its  great  solubility  in  oil,  it  is  held  fast  therein  and  does 
not  penetrate  into  the  bacterial  cells.  Further,  carbolic  acid  pene- 
trates the  bacteria  with  more  difficulty  from  media  containing  much 
proteid  than  it  does  from  pure  water,  for  here  its  chemical  affinity 
to  proteid  more  or  less  neutralizes  its  tendency  to  enter  into  solution 
with  the  lipoids  of  the  bacterial  bodies. 

The  disinfectants  of  the  second  group  form  compounds  with  the 
proteids,  which  are  more  stable  than  the  loose  physicochemieal  com- 
binations formed  by  carbolic  acid  and  proteid,  and  consequently  the 
disinfecting  power  of  metallic  salts  is  even  more  impaired  by  a 
medium  containing  much  proteid  than  is  the  case  with  phenol. 

INFLUENCE  OF  DISSOCIABILITY. — That  the  reactions  of  the  salts  of 
the  heavy  metals,  the  acids,  and  the  alkalies  with  the  proteids  of  the 
bacteria  are  ion  reactions  is  evidenced  by  the  fact  that  the  disinfec- 


502  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

tant  power  of  such  metallic  salts  as  those  of  mercury  is  not  dependent 
solely,  as  was  formerly  believed,  on  the  amount  of  soluble  mercury 
contained  in  their  solutions,  but  runs  parallel  with  the  degree  of  dis- 
sociation of  these  solutions, — i.e.,  is  determined  by  the  concentration 
of  the  free  mercury  ions.  If  the  total  concentration  of  mercury  were 
the  decisive  factor,  it  would  necessarily  follow  that  equimolecular 
solutions  of  different  mercuric  salts  would  exert  equally  powerful 
disinfectant  actions,  but,  as  a  matter  of  fact,  a  comparison  in  the 
toxicity  of  mercury  salts,  which  are  dissociable  in  different  degrees, 
clearly  evidences  the  relationship  between  their  toxicity  and  their 
dissociation  (Paul  u.  Kronig,  Spiro  u.  Scheurlen).  Thus,  according 
to  Hober,  the  degree  of  dissociation  and  the  disinfectant  power  of 
the  three  mercuric  salts,  the  chloride,  the  bromide,  and  the  cyanide, 
decrease  in  the  same  order  (see  table).  The  same  thing  may  be 
shown  for  the  behavior  of  other  metallic  salts, — for  example,  for  the 
salts  of  silver  and  gold. 

Disinfecting  Action  on  Anthrax  Spores 

Number  of  colonies  developing — 
Concentration  of  solution.  After  20  min.  After  85  min. 

HgCl2    1  Mol.:  64 1 7  0 

HgBr.   1  Mol.:   64 1 34  0 

HgCy2  1  Mol. :   16 1 co  33 

There  is,  however,  a  remarkable  exception  from  this  parallelism 
between  disinfecting  power  and  dissociability  of  solutions  of  the  salts 
of  mercury,  for  a  comparison  of  the  disinfecting  power  and  dissocia- 
bility  of  solutions  of  mercuric  chloride  with  those  of  mercuric  nitrate, 
sulphate,  and  acetate,  solutions  of  which  are  much  more  highly  dis- 
sociated, shows  that  the  mercuric  chloride  is  much  the  strongest  dis- 
infectant. 

Disinfecting  Action  on  Anthrax  Spores 

Number  of  colonies  developing — 
Concentration  of  solution.  After  6  min.  After  30  min. 

1  Mol. :   16  I  HgCl2 43  0 

1  Mol.:   16  I  Hg(NO3)2+  HNOS 2000  560 

1  Mol.:   161  HgSO4  +  4H2SO4 1800  592 

1  Mol.:    16  I  Hg(C2HsO2)  +  C2H4O2 2737  1294 

This  exceptional  behavior  of  corrosive  sublimate  is  to  be  attributed 
to  its  solubility  in  lipoids,  a  property  not  possessed  by  those  other 
more  highly  dissociated  salts.  As  a  result  of  this  property,  mercuric 
chloride  penetrates  into  the  bacteria  more  rapidly  than  other  salts, 
and  consequently  its  disinfectant  action  occurs  more  promptly.  How- 
ever, in  case  of  a  more  protracted  action,  such  as  is  of  importance 
in  connection  with  inhibition  by  dilute  solutions  of  the  development 
of  spores,  the  differences  in  the  disinfecting  or  (more  correctly 
speaking)  the  antiseptic  power  of  the  different  salts  disappear. 

The  toxicity  for  tissue  cells  of  the  less  highly  dissociated  quicksilver  com- 
pounds is  also  relatively  slighter,  and  consequently  certain  complex  compounds 
of  the  metallic  salts  act  much  more  mildly  in  the  body.  Dreser  has  shown  that 


. 


GENERAL  ANTISEPTICS  503 


ilutions  of  the  double  salt,  potassium  and  mercury  thiosulphate,  require  a  much 
longer  time  for  the  development  of  their  toxic  actions  on  yeast-cells,  frogs,  and 
fish  than  do  solutions  of  other  salts  of  mercury,  which  contain  the  same  total 
quantity  of  mercury  in  a  more  highly  ionizable  form.  Potassium  and  mercury 
thiosulphate  is  a  complex  salt  which  may  be  looked  upon  as  being  the  potassium 
salt  of  a  mercuric-sulphurous  acid,  which  in  aqueous  solution  is  dissociated  into 
potassium  ions  and  Hg(S2O3)2  ions.  It  is  only  as  a  result  of  the  so-called  second- 
ary dissociation  of  the  complex  mercurial  ions  that  simple  mercury  ions  are  set 
free.  Thus  is  explained  the  lack  of  toxicity  of  this  double  salt  for  cold-blooded 
animals,  although  for  warm-blooded  animals  it  is  almost  as  toxic  as  the  ionizable 
mercury  compounds,  for  in  the  body  of  the  warm-blooded  animal  the  compound 
ion  is  rapidly  decomposed  and  simple  mercury  ions  are  set  free.  In  the  same 
way  other  organic  metal  compounds  lack  both  the  chemical  reactions  of  the  metal 
ions  and  their  physiological  actions,  if  the  metal  is  dissociated  not  as  a  free 
metallic  ion  but  as  a  portion  of  a  complex  one.  Thus,  potassium  ferrocyanide 
neither  gives  the  chemical  reaction  of  iron  directly  nor  does  it  exert  its  physio- 
logical effects,  for  it  is  dissociated  into  potassium  ions  and  ferrocyanide  ions. 

Just  as  with  the  salts  of  the  heavy  metals,  the  disinfectant  action 
of  the  acids  is  determined  chiefly  by  their  dissociability,  for  the  dis- 
infecting power  of  their  solutions  in  general  runs  parallel  with  the 
concentration  of  hydrogen  ions  on  which  their  toxic  action  depends. 
The  highly  dissociable  inorganic  acids,  such  as  hydrochloric,  hydro- 
bromic,  and  sulphuric  acids,  are  powerfully  disinfectant,  while  phos- 
phoric acid  is  much  less  so.  The  organic  ones,  such  as  acetic,  formic, 
and  boric  acids,  are,  however,  far  more  strongly  disinfectant  than 
would  be  expected  from  the  degree  in  which  they  are  dissociated.  As 
was  demonstrated  by  Overton,  the  undissociated  molecules  of  these 
ether-soluble  acids  are  soluble  in  the  lipoids,  and  consequently  pene- 
trate into  the  bacteria  more  readily  than  the  inorganic  acids  which 
are  not  soluble  in  these  lipoids. 

In  an  entirely  similar  fashion  a  comparison  of  the  disinfecting 
power  of  potassium  and  sodium  hydroxide  and  of  ammonia,  as  also 
of  the  hydroxides  of  lithium,  calcium,  strontium,  and  barium,  shows 
that  in  general  the  value  of  the  alkalies  for  disinfection  depends 
on  the  percentage  of  free  hydroxyl  ions  in  their  solutions.  How- 
ever, here  again  the  lipoid  soluble  ammonium  hydroxide  is  an  ex- 
ception, possessing,  in  spite  of  its  slighter  dissociability,  more  power- 
ful disinfectant  action  than  corresponds  to  the  concentration  of  the 
hydroxyl  ions  in  its  solutions. 

Phenol  is  but  slightly  ionized  in  solution,  but  this  is  of  slight 
significance,  for  its  antiseptic  action  is  not  due  to  the  ion  C6H50,  but 
to  the  undivided  molecules.  This  essential  difference  explains  the 
opposite  influence  exerted  by  the  addition  of  salts  on  the  disinfecting 
power  of  solutions  of  salts  of  the  heavy  metals  and  those  of  carbolic 
acid,  for  it  is  possible  to  decrease  the  degree  of  dissociation  of  electro- 
lytes by  adding  to  their  dilute  solutions  (in  which  dissociation  is 
almost  complete)  another  electrolyte  possessing  a  common  ion.  Thus, 
a  portion  of  the  free  mercury  ions  in  solutions  of  HgCl2  may  be  forced 
back  into  molecular  combination  by  the  addition  of  NaCl,  and  in  this 
way  both  the  degree  of  dissociation  and  the  disinfecting  power  of  the 
solution  may  be  diminished. 


504  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

Disinfection  Experiments  with  Anthrax  Spores. 

Colonies  develop- 
ing after  6  min. 
HgCb  Concentration  expos. 

HgCl2    1  Mol. :  16  I  8 

HgCl2  +  NaCl     1  Mol.:  16 1  32 

HgCl2  +  2NaCl 1  Mol. :  16  I  124 

HgCl2  +  4NaCl     1  Mol. :  16  I  382 

HgCl2  +  lONaCl   1  Mol.:  16  I  1087 

(After  Paul  u.  Kronig) 

The  disinfecting  powers  of  solutions  of  carbolic  acid  are  altered 
in  an  opposite  direction  by  the  addition  of  salt  (Scheurlen),  for,  in 
the  case  of  carbolic  acid,  the  cresols,  etc.,  the  addition  of  salt 
markedly  increases  the  disinfecting  power  of  their  solutions,  this 
effect  being  produced  not  only  by  sodium  chloride  but  by  all  salts. 
The  augmentation  of  the  disinfectant  action  runs  parallel  with  the 
"salting  out"  power  of  the  salts,  for  by  this  action  the  solubility 
of  the  carbolic  acid  in  the  water  is  diminished,  and  thus  the  partition 
coefficient  between  the  medium  and  the  cells  is  altered,  so  that  the 
phenol  penetrates  into  the  bacteria  in  larger  amounts  than  before 
(Spiro  u.  Brims). 

Disinfection  Experiments  with  Anthrax  Bacilli 

Number  of  colonies  after — 

Solution  1  day  3  days  5  days 

\%  phenol     1520  1950  1650 

\%  phenol  +  24%  NaCl     96  0  0 

2%  phenol  +  20%  NaCl     1560  120  0 

3%  phenol    1200  1120  1010 

3%  phenol  +  12%  NaCl     0  0  0 

INFLUENCE  OF  SURROUNDING  MEDIA. — From  the  above  it  may  be 
concluded  that  the  action  of  the  antiseptics  on  bacteria  is  due  to  their 
chemical  and  physicochemical  affinity  to  various  constituents  of  the 
bacterial  bodies.  If  these  affinities  find  similar  opportunities  for 
chemical  or  physical  combination  with  substances  present  in  the 
complicated  organic  culture-medium,  there  results  a  rivalry  between 
those  constituents  of  the  bacteria  and  those  of  the  culture-medium 
which  are  capable  of  reacting  with  the  disinfectants.  Consequently  it 
is  clear  that  the  efficiency  of  the  antiseptics  will  depend  not  alone  on 
their  concentration  and  the  duration  of  their  action,  but  also  on  the 
chemical  composition  of  the  medium  in  which  they  act.  Their  full 
power  can  be  exerted  only  in  aqueous  solutions,  and  their  action  is 
much  weaker  in  culture-media  which  contain  considerable  amounts  of 
organic  substances,  particularly  proteids.  Herein  lies  the  almost  in- 
surmountable difficulty  which  opposes  a  disinfection  in  the  living  body. 

Behring,  for  one,  hag  shown  that  a  twofold  to  fourfold  higher  concentration 
of  corrosive  sublimate  is  needed  to  kill  spores  in  blood-serum  than  to  do  the  same 
in  distilled  water.  Anthrax  bacilli  in  aqueous  media  are  killed  even  by  1-500,000 
HgCljj,  but  in  bouillon  only  by  a  concentration  of  1-40,000,  while  in  blood-serum 
with  the  same  length  of  exposure  even  1-2000  is  no  longer  efficient. 


GENERAL  ANTISEPTICS  505 

The  influence  of  the  medium  expresses  itself  in  different  fashions 
according  to  the  mechanism  by  which  the  antiseptic  action  is  produced. 
It  is  particularly  the  proteid  substances  present  in  the  secretions  of 
wounds  and  in  the  tissue  cells  which  divert  the  metallic  ions  away 
from  the  bacteria,  and,  as  the  albuminates  form  stable  compounds 
with  the  salts  of  the  metals,  the  antiseptic  power  of  such  solutions 
is  permanently  diminished  in  proportion  to  the  amounts  of  the 
metals  which  combine  with  them.  It  is  for  the  same  reasons  that 
iodine,  which  in  a  culture-medium  containing  but  little  proteid 
exerts  a  powerful  disinfecting  action,  does  so  but  feebly  in  the 
presence  of  much  proteid.  On  the  other  hand,  the  antiseptic  action 
of  the  ethereal  oils  which  do  not  combine  with  proteids  is  much  less 
impaired  by  them. 

BIBLIOGRAPHY 

Bokorny:  Pfliiger's  Arch.,  1896,  vol.  64,  p.  262;  1905,  vol.  108,  p.  216. 

Czapek:  Biochem.  d.  Pflanzen,  p.  857. 

Dreser:  Arch.  f.  exp.  Path.  u.  Pharm.,  1893,  vol.  32. 

Fischer,  A.:   Sitz.-Bericht  d.  kgl.  Sachs.  Ges.  d.  Wiss.,  1891. 

Fischer,  A.:   Ztschr.  f.  Hygiene,  1900,  vol.  35. 

Geppert:   Berl.  klin.  Woch.,  1890,  No.  11. 

Hober:  Physikal.  Chemie  d.  Zelle  u.  d.  Gewebes,  2d  edition,  Leipzig,  1906,  p.  261. 

Koch:  Mitteil.  aus  dem  kais.  Gesundheitsamt,  1886,  vol.  1. 

Overton:  Vierteljarhschr.  d.  Naturforscher-Ges.  in  Zurich,  1899. 

Overton:   Pfliiger's  Arch.,  1902,  vol.  92,  p.  115. 

Paul  u.  Kronig:   Ztschr.  f.  physik.  Chem.,  1896,  vol.  12. 

Paul  u.  Kronig:  Munchn.  med.  Woch.,  1897. 

Paul  u.  Kronig:   Ztschr.  f.  Hyg.,  1897,  vol.  25. 

Scheuerlen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  37,  p.  74. 

Spiro  u.  Bruns:  Arch.  f.  exp.  Path.  u.  Pharm.,  1898,  vol.  41,  p.  355. 

Spiro  u.  Scheuerlen:   Miinchn.  med.  Woch.,  1897. 

CONSIDERATION  OF  THE  INDIVIDUAL  ANTISEPTICS 
It  will  be  sufficient  for  our  purpose  merely  to  name  the  more 
important  antiseptics,  and  to  discuss  the  actions  of  certain  typical 
representatives  of  the  different  groups.  The  choice  of  an  antiseptic 
will  depend  on  the  purpose  for  which  it  is  to  be  used,  certain  of  them 
being  employed  for  the  destruction  of  micro-organisms  outside  of  the 
body,  while  others  are  used  for  the  purpose  of  preventing  their 
development  in  wounds  and  on  mucous  membranes. 

CHLORINE  is  the  most  powerful  and  energetic  disinfectant  which 
>re  possess,  but  it  also  exerts  a  destructive  action  on  all  organic 
material.  It  is  a  yellowish-green  gas,  with  a  suffocating  odor  and 
very  irritant  to  the  mucous  membranes,  which,  in  the  presence  of 
moisture,  is  an  extremely  efficient  disinfectant,  most  bacteria  and 
their  spores  being  killed  by  concentration  of  3  per  cent,  of  chlorine 
gas  in  the  atmosphere.  Bromine  acts  less  energetically,  and  iodine 
still  more  weakly  (Geppert,  Paul  u.  Kronig}. 

The  employment  of  chlorine  for  the  disinfection  of  various  ob- 
jects, living-rooms,  etc.,  is  very  much  limited  by  its  destructive  effect. 
Where,  however,  this  is  of  no  importance,  as  in  the  disinfection  of 


506  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

fasces,  etc.,  one  frequently  uses  chlorinated  lime,  a  mixture  of  calcium 
hypochlorite,  calcium  chloride,  and  lime,  which  when  treated  with 
acids — on  addition  of  HC1 — gives  off  free  chlorine.  A  freshly  pre- 
pared solution  of  potassium  permanganate  on  the  addition  of  0.9 
per  cent.  HC1  also  gives  off  free  chlorine,  which  may  be  used  for 
the  disinfection  of  the  hands  (Paul  u.  Kronig). 

Chlorine  water,  Liquor  chlori  compositus,  a  yellowish-green,  very 
irritating  fluid,  with  a  suffocating  odor,  containing  0.4  per  cent, 
chlorine,  is  used  as  a  corrosive  and  disinfectant  in  wounds  and  on 
mucous  membranes,  and  was  formerly  employed  as  an  intestinal  dis- 
infectant. 

In  the  presence  of  water,  chlorine  oxidizes  all  organic  material, 
for,  by  virtue  of  its  strong  affinity  to  hydrogen,  it  liberates  nascent 
oxygen  from  the  water. 

Even  very  small  amounts  of  chlorine  gas  irritate  the  mucous  membranes 
of  the  eye  and  nose,  and,  if  somewhat  larger  amounts  are  present  in  the  atmos- 
phere, they  cause  the  well-known  protective  reflexes,  dyspnoea  and  coughing. 
When  stronger  concentrations  are  inhaled,  they  may  cause  bronchitis  and  pneu- 
monia. When  chlorine  is  present  in  the  air,  its  irritating  effects  may  be  dimin^ 
ished  by  sprinkling  ammonia  about  so  as  to  form  the  now  volatile  ammonium 
chloride. 

BIBLIOGRAPHY 

Geppert:   Berl.  klin.  Woch.,  1890. 

Paul  u.  Kronig:   Ztschr.  f.  Hyg.,  1897,  vol.  25. 

SULPHUROUS  ACID,  H2S03,  whose  gaseous  anhydride,  sulphur 
dioxide,  S02,  is  formed  by  the  combustion  of  sulphur,  is  at  present 
hardly  used  at  all  for  the  purpose  of  disinfecting  residences.  [Sul- 
phurous acid  is  the  best — and  in  fact  the  only  practical — means  of 
killing  the  yellow-fever  carrier,  stegomyia  fasciata,  and  in  spite  of 
its  disadvantages  it  is  used  for  this  purpose,  even  in  living-rooms. 
When  thus  employed  all  metallic  objects  and  readily  injured  fabrics 
should,  if  possible,  be  removed  from  the  room. — TR.]  It  is  a 
powerful  reducing  agent,  and,  by  virtue  of  this  property,  is  an 
efficient  means  of  preventing  fermentation,  and  is  used  for  this 
purpose  in  the  preparation  of  wine  casks.  It  is  a  particularly  power- 
ful poison  for  moulds. 

QUICKLIME,  CaO,  is  used  as  an  inexpensive  means  of  disinfecting 
large  quantities  of  material,  such  as  privy  vaults  or  the  stools  of 
typhoid  patients,  etc.  It  acts  as  a  bactericide  by  virtue  of  its  dehy- 
drating power,  and,  after  its  transformation  by  the  water  into  slaked 
lime,  calcium  hydrate,  Ca(OH),  as  a  powerful  alkali  destroys  the 
bacteria.  Finely  powdered  calcium  hydrate  suspended  in  water  in  a 
concentration  of  20  per  cent,  is  known  as  milk  of  lime,  and  its  clear 
solution,  containing  about  0.17  per  cent,  of  calcium  hydroxide,  is 
known  as  lime  water. 

CRUDE  MINERAL  ACIDS  are  adapted  for  disinfection  en  masse. 


GENERAL  ANTISEPTICS  507 

CRUDE  SULPHATE  OF  IRON  acts  chiefly  as  a  deodorizer  by  virtue  of 
its  power  of  combining  with  sulphuretted  hydrogen:  and  ammonium 
sulphide. 

FORMALDEHYDE  is  an  extremely  valuable  disinfectant  for  in- 
animate objects.  It  is  a  colorless  gas  which  is  very  irritant  to  the 
conjunctiva  and  nasal  mucosa,  and  when  dissolved  in  water  is 
a  very  powerful  antiseptic  and  also  a  sufficiently  powerful  bacter- 
icide.  Anthrax  bacilli  are  killed  in  one  hour  by  a  dilution  of  1  to 
2000  and  their  spores  by  1  to  1000.  This  drug  readily  penetrates 
into  the  bacterial  bodies,  and  reacts  with  numerous  organic  sub- 
stances and  in  particular  coagulates  proteid.  It  is  very  irritant  to 
animal  tissues,  but  after  absorption  is  relatively  non-toxic  to  the 
central  nervous  system,  as  it  is  almost  completely  decomposed  in  the 
body,  only  a  small  portion  being  excreted  as  formic  acid.  Another 
small  portion  is  probably  excreted  in  unaltered  form,  as  after  in- 
gestion  of  formaldehyde  the  urine  is  weakly  antiseptic.  Used  ex- 
ternally formaldehyde  hardens  or  tans  the  skin,  and  consequently 
sweat  secretion  may  be  diminished  by  bathing  the  skin  with  its 
solutions.  Formaline  or  formol  is  a  40  per  cent,  (by  volume)  aqueous 
solution  of  formaldehyde. 

In  y2  to  1  per  cent,  aqueous  solutions  formaldehyde  is  used  for 
the  disinfection  of  mucous  membranes,  but  it  is  chiefly  employed  for 
the  disinfection  of  residences,  etc.  Generated  with  steam  and  in- 
troduced into  hermetically  closed  rooms,  formaldehyde  produces  a 
reliable  surface  disinfection,  for  in  gaseous  form  it  reaches  the 
surfaces  of  all  the  objects  which  are  to  be  disinfected,  and  is  de- 
posited on  them  dissolved  in  extremely  small  drops  of  water.  How- 
ever, this  method  of  disinfection  does  not  exert  any  considerable 
disinfection  except  on  the  surface  of  the  various  objects.  When  the 
rooms  are  opened  again  the  suffocating  and  irritating  formaldehyde 
vapor  and  odor  may  be  removed  by  the  use  of  ammonia  vapor,  which 
combines  with  formaldehyde  forming  the  non-volatile  hexamethyl- 
enamine. 

IN  DISINFECTION  OF  THE  SKIN,  either  that  of  the  hands  of  the 
operator  or  the  skin  of  the  field  of  operation,  the  greatest  emphasis 
is  at  present  laid  upon  an  energetic  mechanical  cleansing,  which 
should  be  followed  by  a  chemical  disinfection  in  order  to  lessen 
as  far  as  possible  the  number  of  germs  hidden  in  the  pores  and 
glandular  canals  of  the  skin.  Although  complete  freedom  from  such 
germs  cannot  be  obtained,  alcohol  and  corrosive  sublimate  have  been 
shown  by  bacteriological  investigation  of  disinfection  of  the  hands 
to  be  the  best  substances  for  this  purpose  (Paul  u.  Sarwey}.  Even 
in  a  concentration  of  5  per  10  per  cent,  ethyl  alcohol  inhibits  the  de- 
velopment of  bacteria,  but  its  disinfecting  power  increases  with  its 
concentration  only  up  to  a  certain  fixed  point,  and  absolute  alcohol 
exerts  very  slight  disinfecting  actions.  In  the  strength  of  50  per  cent. 


508  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

it  occupies  a  position  midway  between  1-1000  corrosive  sublimate 
and  3  per  cent,  carbolic  acid. 

In  the  disinfection  of  the  hands,  in  addition  to  its  bactericidal 
power,  alcohol's  property  of  dissolving  the  fatty  skin  secretions  is  of 
considerable  importance,  as  is  its  power  of  penetrating,  the  skin,  by 
virtue  of  which  property  it  is  able  to  attack  the  bacteria  in  the 
deeper  layers  of  the  skin  and  to  open  the  path  for  other  disinfectants 
which  may  be  used  later  (Furbringer,  Ahlfeld,  Mikulicz). 

BIBLIOGRAPHY 

Ahlfeld:  Monatschr.  f.  Geb.  u.  Gyn.,  1899,  vol.  10. 

Furbringer:   Deut.  med.  Woch.,  1899,  No.  49. 

Mikulicz:  Deut.  med.  Woch.,  1899,  No.  24. 

Paul  u.  Sarwey:  Miinchn.  med.  Woch.,  1899,  No.  51;  1901,  No.  36. 

THE  DISINFECTION  OF  INSTRUMENTS  AND  OTHER  OBJECTS,  particu- 
larly those  which  may  come  in  contact  with  wounds,  may  be  accom- 
plished by  the  use  of  3  to  4  per  cent,  carbolic  acid  solutions,  by  lysol, 
and  by  other  aromatic  antiseptics,  as  also  by  1  to  1000  sublimate 
solutions,  which  latter  should  not  be  used  on  metal  instruments  as 
they  form  amalgams  with  the  metals.  The  same  substances  in  weaker 
concentrations  are  also  used  in  wounds  as  antiseptics. 

IN  THE  DISINFECTION  OF  MUCOUS  MEMBRANES  AND  WOUNDS  the  US6 

of  higher  concentrations  of  the  stronger  disinfectants  is  contraindicated, 
by  the  unavoidable  damage  to  the  tissues  produced  by  these  general 
cell  poisons  and  by  the  danger  of  systemic  poisoning  from  their 
absorption.  While  the  antiseptics  cause  actual  destruction  of  the 
tissue  only  in  concentrations  considerably  stronger  than  those  which 
prevent  the  development  of  bacteria,  these  drugs  are  all  general 
cell  poisons,  and,  even  in  very  weak  solutions,  impair  the  vital 
functions  of  the  tissues  and  thus  interfere  with  their  natural  pro- 
tective reactions  and  consequently  prepare  a  favorable  culture- 
medium  for  bacteria. 

It  is  for  this  reason  that  the  modern  surgeon  has  given  his  pre- 
ference to  aseptic  measures  and  has  correctly  abandoned  the  employ- 
ment of  antiseptics  in  the  treatment  of  wounds.  Even  for  the 
purpose  of  cleansing  already  infected  wounds,  the  methods  formerly 
commonly  employed  in  the  attempt  to  secure  energetic  disinfection 
have  been  abandoned,  and  to-day,  in  place  of  1-1000  bichloride  or 
3  per  cent,  phenol  or  lysol  solutions,  much  weaker  solutions  or  milder 
antiseptics,  like  hydrogen  peroxide,  aluminum  acetate,  or  boric  acid, 
are  employed  for  the  purpose  of  cleansing  wounds  of  their  germs. 
These  weaker  concentrations  are  scarcely  able  to  inhibit  the  develop- 
ment of  bacteria,  and  perhaps  in  the  treatment  of  wounds  play  only 
the  role  of  sterile  cleansing  fluids. 

Moreover,  in  view  of  the  rapidity  with  which  bacteria  multiply, 
it  would  not  be  possible  to  obtain  a  radical  purification  of  wounds 
even  by  the  use  of  the  stronger  concentrations  (Schimmelbusch) ,  and 


GENERAL  ANTISEPTICS  509 

damage  done  to  the  tissue  cells  by  such  procedures  would  en- 
inger  the  healing  of  wounds,  which,  as  a  rule,  are  able  by  them- 
selves to  destroy  the  invading  bacteria.  A  destruction  of  bacteria 
within  the  tissues  of  the  human  body  by  general — that  is,  by  non- 
specific— disinfectants  is  possible  only  in  those  cases  in  which  one 
is  willing  to  accomplish  this  at  the  cost  of  the  sacrifice  of  tissue  cells 
which  are  capable  of  regeneration,  and  consequently  is  of  slight 
value.  Examples  of  this  would  be  the  application  of  the  tincture  of 
iodine  to  the  skin  for  the  purpose  of  making  an  incision  through 
tissues  which  are  certainly  free  of  bacteria,  or  the  treatment  of 
diphtheria  by  the  local  application  of  caustics  for  the  purpose  of 
killing  the  bacilli  at  the  same  time  with  the  tissues. 

The  employment  of  antiseptics  in  wounds  and  mucous  membranes, 
as  has  already  been  mentioned,  is  still  further  limited  by  the  danger 
of  systemic  poisoning  as  a  result  of  their  absorption.  This  may  be 
prevented  if  the  distoxication  of  the  antiseptic — by  its  elimination  or 
chemical  transformation — keeps  pace  with  its  absorption  and  thus  pre- 
vents the  attainment  in  the  blood  of  a  toxic  threshold  value.  Theo- 
retically this  indication  is  best  met  by  hydrogen  peroxide,  which,  as 
soon  as  it  comes  in  contact  with  the  tissues,  is  decomposed  into  water 
and  oxygen.  Unfortunately,  at  the  same  time  its  local  disinfecting 
power  is  diminished. 

Formaldehyde  and  potassium  permanganate  also  cause  only  local 
damage  to  the  tissues  and  no  harmful  systemic  effects.  Unfortu- 
nately, the  most  reliable  antiseptics,  bichloride,  carbolic  acid,  etc., 
owing  to  their  lipoid  solubility  are  readily  absorbed.  Perhaps  it  would 
be  worth  while  to  try  and  see  if,  like  cocaine,  they  could  be  retained 
longer  at  the  point  of  application  by  the  addition  of  epinephrin  to 
their  solutions,  and  if  the  absorption  of  sufficiently  concentrated  solu- 
tions could  be  thus  retarded. 

As  a  rule,  when  toxic  quantities  of  the  general  cell  poisons  are  absorbed, 
it  is  the  central  nervous  system  which  is  most  affected,  and  after  it  the  organs 
of  elimination,  as  during  their  elimination  these  poisons  accumulate  in  these 
cells  in  somewhat  high  concentrations. 

BIBLIOGRAPHY 
Schimmelbusch :   Fortschr.  d.  Med.,  1895. 

BORIC  ACID,  H3B03,  is  soluble  in  20  parts  of  water  at  ordinary- 
temperatures.  Solutions  of  1  to  3  in  100  are  simply  antiseptic  and 
not  bactericidal.  As  this  weakly  dissociated  acid  produces  hardly 
any  corrosive  effect,  it  does  not  damage  the  tissues,  and  may  be  ap- 
plied to  surfaces  of  wounds  and  even  such  mucous  membranes  as 
the  conjunctiva,  or  be  used  to  wash  out  the  stomach,  the  bladder, 
the  uterus,  etc.  However,  it  must  not  be  forgotten  that  boric  acid  is 
by  no  means  lacking  in  toxicity,  for  in  larger  doses  it  causes  gastro- 


510          ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

intestinal  irritation,  and,  when  considerable  amounts  of  its  solutions 
have  been  left  in  body  cavities,  it  has  in  a  number  of  cases  caused 
fatal  poisoning. 

Borax,  biborate  of  soda,  Na2B407  -f-  10H20,  by  virtue  of  its  weak 
elective  reaction,  acts  somewhat  antiseptically,  and  is  particularly 
effective  against  moulds  and  yeast-fungi,  and  is  consequently  used  in 
the  treatment  of  thrush. 

Boric  Acid  and  Borax  as  Preservatives  for  Food. — As  a  con- 
sequence of  their  relative  lack  of  toxicity,  boric  acid  and  borax  have 
been  widely  used  as  preservatives  for  meats,  sausages,  preserves,  and 
so  forth.  Borax  is  also,  though  improperly,  used  as  a  preservative 
for  milk,  in  which  it,  like  all  alkaline  salts,  impairs  the  coagulability 
of  casein.  The  presence  of  either  of  these  substances  in  food  is  not 
betrayed  either  by  taste  or  smell,  but  in  order  tQ  be  effective  they  must 
be  added  in  amounts  ranging  from  5  to  30  parts  in  the  thousand. 
Consequently,  as  they  are  so  generally  employed  for  the  preservation 
of  our  most  important  food-stuffs,  it  is  possible  that  as.  much  as 
several  grammes  may  be  ingested  daily,  and  such  doses  when  taken 
continually  are  by  no  means  harmless,  particularly  inasmuch  as  boric 
acid  is  slowly  excreted,  and  consequently  can  accumulate  in  con- 
siderable amounts  in  the  organism. 

According  to  the  investigations  of  Rost,  Rubner,  and  others,  even 
daily  doses  of  0.5  to  1.0  gm.  of  boric  acid  exert  a  deleterious  effect 
upon  the  utilization  of  the  food,  and  augment  the  combustion  of 
nutrient  material,  particularly  that  of  non-nitrogenous  substances, 
such  as  fat.  Even  in  healthy  individuals  considerable  loss  of  weight 
results  after  5-12  days  from  the  administration  of  0.3  gm.  daily, 
and  in  nephritic  patients,  in  whom  its  excretion  is  retarded,  the 
harmful  results  may  be  even  more  serious.  These  facts  entirely 
justify  the  prohibition  of  its  use  as  a  preservative  for  food. 

BIBLIOGRAPHY 

Rost:  Arb.  aus  d.  kais.  Gesundheitsamt,  1902,  vol.  19. 

Rost:  Deut.  med.  Woch.,  1903,  No.  7. 

Rost:  Arch,  intern,  de  Pharmacodynamie,  1905,  vol.  15. 

THE  SULPHITES  also,  particularly  sodium  sulphite,  are  much  used 
as  preservatives  for  meat  in  amounts  which  often  reach  to  4  to  20 
parts  per  1000.  Although  large  doses  of  sulphites  can  produce  gen- 
eral harmful  effects  (Pfeiffer,  Rost),  in  view  of  the  rapid  and  almost 
complete  transformation  of  the  sulphites  into  the  harmless  sulphates 
(Franz  u.  Sonntag),  it  is  still  an  open  question  whether  the  amounts 
necessary  for  the  preservation  of  food-stuffs  are  sufficient  to  cause 
harmful  effects. 

[Even  Wiley's  own  figures  obtained  in  his  experiments  with  the 
famous  "poison  squad,"  when  carefully  examined,  fail  to  support 
his  claim  that  the  sulphites,  in  moderate  amounts,  are  deleterious.— 
TR.] 


GENERAL  ANTISEPTICS  511 

BIBLIOGRAPHY 

Franz  u.  Sonntag:   Arb.  aus  d.  kais.  Gesundheitsamt,  1908,  vol.  28,  p.  225. 
Pfeiffer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  27,  p.  261. 
Host:  Arb.  aus  d.  kais.  Gesundheitsamt,  1904,  vol.  21. 

HYDROGEN  PEROXIDE. — Oxidizing  agents,  by  liberating  nascent 
oxygen,  act  as  disinfectants  in  a  fashion  fundamentally  similar  to 
chlorine.  Hydrogen  peroxide,  which  is  decomposed  with  extreme 
readiness  into  water  and  oxygen,  is  the  most  powerful  of  these  agents 
which  may  be  employed  in  medicine.  In  aqueous  solution  it  is  de- 
composed with  a  very  active  liberation  of  oxygen  by  catalase,  a 
ferment  present  in  all  cells,  and  also  by  many  inorganic  substances 
which  in  a  state  of  very  fine  subdivision  act  like  ferments. 

This  nascent  oxygen  acts  as  a  disinfectant,  but,  as  the  action 
is  limited  to  the  short  period  during  which  the  gas  is  generated,  it 
can  act  only  momentarily  and  superficially.  This  substance  is  suit- 
able for  use  as  a  mouth-wash  or  gargle,  or  as  a  means  of  moistening 
dressings,  for  nascent  oxygen  destroys  disagreeable-smelling  and 
toxic  decomposition  products. 

When  injected  into  closed  body  cavities,  siich  as  the  peritoneal  cavity, 
hydrogen  peroxide  in  unaltered  form  may  enter  the  blood  and  cause  sudden  death 
as  a  result  of  the  generation  of  gaseous  oxygen  in  the  blood. 

Ferments,  too,  are  rapidly  destroyed  by  hydrogen  peroxide.  Its  employment 
as  a  preservative  for  milk  prevents  souring,  but  at  the  same  time  destroys  the 
enzymes  and  antitoxic  substances  normally  present  in  milk. 

POTASSIUM  PERMANGANATE,  KMn04,  also  acts  as  an  oxidizing 
agent,  which  is  very  readily  reduced  by  proteid  as  well  as.  by  all 
other  labile  organic  substances.  The  manganese  oxide,  which  re- 
sults from  this  reduction,  forms  a  brown  precipitate,  causing  brown 
spots  on  the  skin  and  elsewhere.  Even  1  per  cent,  solutions  cause 
a  caustic  action  on  the  surfaces  of  wounds  and  mucous  membranes, 
but  in  a  concentration  of  1  to  1000  it  deodorizes  foul-smelling  putre- 
faction products  and  exerts  a  weak  disinfectant  action.  It  may 
consequently  be  used  for  the  washing  of  wounds  and  mucous  mem- 
branes or  as  a  mouth-wash,  etc. 

In  this  connection,  mention  should  be  made  of  the  employment  of  potassium 
permanganate  as  an  antidote  in  poisoning  by  phosphorus,  morphine,  and  other 
toxic  substances,  which  are  readily  oxidized  and  rendered  non-toxic,  but  benefit 
may  be  expected  from  its  employment  only  if  these  poisons  are  still  present  in 
the  stomach.  Potassium  cyanide  also  is  transformed  by  it  into  the  less  toxic 
potassium  cyanate. 

POTASSIUM  CHLORATE,  KC103,  is  weakly  antiseptic  by  virtue  of 
its  oxidizing  powers.  When  heated,  it  oxidizes  so  energetically  that, 
when  mixed  with  readily  combustible  substances,  an  explosion  may 
result  from  such  slight  warming  as  is  produced  by  their  trituration 
in  a  mortar.  In  the  body  it  gives  off  its  oxygen  very  slowly  and  is  in 
largest  part  (about  90  per  cent.)  excreted  in  the  urine.  Even  in 
strong  concentrations  it  hardly  inhibits  the  growth  of  bacteria,  and 


512  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

consequently  it  is  questionable  whether,  when  used  as  a  gargle,  it 
acts  better  than  solutions  of  indifferent  salts.  Formerly  curative 
effects  in  diphtheria  were  attributed  to  its  action  after  absorption, 
and  even  now  it  is  administered  in  doses  of  4  to  6  gm.  per  diem  in 
pyelitis  and  cystitis,  with  the  idea  that  it  endows  the  urine  with 
antiseptic  properties.  Its  internal  administration  in  doses  of  more 
than  8  gm.  per  diem  [or  in  much  smaller  doses. — TE.]  is  under 
all  circumstances  attended  by  great  danger,  and  with  impaired 
renal  function  even  smaller  doses  are  dangerous  (Quincke). 

After  absorption  potassium  chlorate  penetrates  into  the  red  blood-cells 
with  relative  ease  and  transforms  the  haemoglobin  into  methaemoglobin,  so  that 
the  blood  acquires  a  brownish  color  and  the  spectroscope  shows  a  characteristic 
narrow  stripe  in  the  red  portion  of  the  spectrum.  When  this  action  is  pro- 
duced in  a  sufficient  degree,  all  the  symptoms  of  methsemoglobinaemia  result  (see 
p.  45 1 ) .  In  very  acute  cases  internal  asphyxia  results  and  death  occurs  in  a  few 
hours.  In  somewhat  more  protracted  cases  hemorrhages,  diarrhoea,  vomiting 
of  greenish-black  material,  and  all  the  other  results  of  the  destruction  of  the 
red  cells  occur.  Agglutination  of  the  red  cells  occurs,  causing  thrombi,  infarcts, 
and  ecchymoses,  and  the  broken-dpwn  cells  are  deposited  in  the  organs  which 
normally  destroy  them,  while  the  liver  and  spleen  become  swollen  and  jaundice 
develops. 

The  urine  acquires  a  reddish-brown  to  black  color  and  contains  proteid, 
broken-down  red  cells,  methaemoglobin,  and  hsematin,  and,  as  a  result  of  blocking 
of  the  renal  tubules,  anuria  and  death  with  uraemic  symptoms  result.  Doses 
which  exceed  10  gm.  can  cause  severe  poisoning,  while  15  to  20  gm.  are,  as  a 
rule,  fatal.  The  treatment  can  consist  only  in  stimulation  of  diuresis  to 
accelerate  the  elimination  of  the  poisons,  but  bleeding  and  saline  infusions  are 
also  recommended. 

As  in  various  infectious  diseases  the  red  blood-corpuscles  have  to 
some  extent  become  more  permeable  to  various  salts,  the  internal  ad- 
ministration of  potassium  chlorate  in  these  conditions  is  contrain- 
dicated,  just  as  it  is  in  nephritis.  Moreover,  the  use  of  large  quan- 
tities of  potassium  chlorate  solutions  as  a  gargle  has  often  caused 
serious  poisoning,  particularly  in  children,  as  a  result  of  the  unavoid- 
able swallowing  of  the  drug. 

BIBLIOGRAPHY 
Quincke:  Deut.  Arch.  f.  klin.  Med.,  1904,  vol.  79,  p.  290. 

MERCURIAL  SALTS 

In  vitro  the  soluble  and  dissociable  mercury  compounds  are  power- 
ful disinfectants,  but  the  proteids  present  in  wound  secretions  very 
markedly  lessen  their  disinfecting  power.  Corrosive  sublimate,  the 
bichloride  of  mercury,  HgCl2,  which  is  soluble  in  17  parts  of  cold 
water,  and  the  other  soluble  mercuric  salts  damage  the  cells  of  the 
tissues  even  in  those  low  concentrations  which  prevent  the  develop- 
ment of  bacteria.  Moreover,  the  employment  of  larger  quantities  of 
even  dilute  solutions  of  these  salts  is  limited  by  the  danger  of  their 
absorption,  which  is  especially  great  when  they  are  used  for  wash- 
ing out  large  wounds  or  mucous  membranes. 


GENERAL  ANTISEPTICS  513 

Bichloride  of  mercury  with  proteids  forms  albuminates  which 
rith  an  excess  of  proteid  and  sodium  chloride  form  soluble  double 
salts  of  mercury  albuminate  and  NaCl.  As  a  consequence,  the  coagu- 
lum  at  first  formed  by  their  local  action  soon  goes  into  solution  and  is 
absorbed,  and,  as  a  result,  numerous  acute  and  subacute  mercurial 
poisonings  have  occurred,  particularly  after  the  postpartum  use  of  a 
bichloride  solution  as  an  intra-uterine  douche. 

For  the  purpose  of  preventing  the  formation  of  insoluble  mercury 
albuminates,  sodium  chloride  is  added  to  bichloride  solutions,  many 
of  the  bichloride  tablets  containing  this  salt,  although  the  disin- 
fectant power  is  impaired  by  this  addition.  Recently,  in  place  of 
the  sublimate  a  compound  of  mercuric  sulphate  with  ethylenediamine 
has  been  recommended  under  the  name  of  sublamine,  which,  being 
a  complex  mercuric  salt,  does  not  precipitate  proteid  or  cause  irrita- 
tion of  the  tissues. 

MERCURIAL  POISONING. — When  large  quantities  of  mercury  are  rapidly 
absorbed,  the  systemic  effects  are  exerted  principally  on  the  central  nervous 
system  and  the  organs  of  elimination,  in  this  case  chiefly  the  large  intestine 
and  the  kidneys.  As  a  result  of  the  accumulation  of  relatively  large  amounts 
of  mercury  in  the  cells  through  which  this  metal  is  excreted,  these  cells  undergo 
necrosis,  and  nephritis  and  colitis  result,  the  latter  causing  abdominal  pain, 
tenesmus,  and  diarrhoea  containing  blood  and  shreds  of  the  mucous  membranes. 
The  toxic  action  on  the  central  nervous  system  expresses  itself  in  a  condition 
of  stupor  or  apathy  and  finally  by  collapse,  as  a  result  of  which  the  patient 
dies  with  a  subnormal  temperature  usually  only  after  5-10  days.  Post  mortem 
one  finds  hemorrhagic  diphtheritic  inflammation  of  the  caecum  and  colon  and 
parenchymatous  nephritis,  often  with  calcium  infarcts  in  the  kidneys,  as  a 
result  of  the  deposition  of  calcium  phosphate  and  carbonate  in  the  necrotie  renal 
epithelium.  When  rapidly  absorbed,  0.1  gm.  of  bichloride  may  produce  fatal 
poisoning.  The  maximal  dose  of  the  soluble  mercuric  salts  is  0.02  gm.  per  dose, 
0.06  gm.  per  diem. 

In  less  acute  cases  the  first  symptoms  noted  are  those  of  the  mercurial 
stomatitis,  salivation,  metallic  taste,  and  disagreeable  odor  in  the  mouth,  with 
redness  and  swelling  of  the  gums  and  tongue.  In  such  cases  the  symptoms  due 
to  intestinal  and  renal  lesions  appear  only  some  days  later.  The  accumulation 
of  mercury  in  the  body  as  a  result  of  its  long-continued  administration  and 
chronic  mercury  poisoning  are  described  on  pages  415  and  542. 

SILVER  SALTS. — The  dissociable  and  soluble  silver  salts  are  also 
very  strongly  antiseptic,  preventing  the  development  of  many 
bacteria  even  in  the  blood-serum  and  in  a  dilution  of  1  to  80,000. 
Silver  lactate  (actol)  and  silver  citrate  (itrol)  are  preferred  by  some 
surgeons  to  corrosive  sublimate. 

Silver  nitrate  in  different  concentrations  is  used  for  the  disin- 
fection of  mucous  membranes, — for  example,  in  2  per  cent,  solution 
as  a  means  of  preventing  gonorrhceal  ophthalmia  in  the  new-born, 
and  in  2-4  per  cent,  solutions  in  the  treatment  of  urethral  gon- 
orrhoea.* However,  when  thus  used  its  action  is  confined  to  the 

*  [The  astringent  and  disinfectant  actions  of  silver  compounds  do  not 
account  entirely  for  their  almost  specific  effects  in  gonorrhceal  inflammations. 
It  is  highly  probable  that  they  owe  much  of  their  curative  action  to  their  power 
of  attracting  the  leucocytes  to  them, — i.e.,  to  their  chemotacic  powers. — TB.] 

33 


514  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

surface  of  the  mucous  membranes,  as  silver  combines  with  proteid  and 
sodium  chloride.  As  the  organic  silver  compounds  do  not  directly 
combine  with  proteid  and  NaCl,  such  compounds  as  protargol,  a  solu- 
tion of  an  albuminate  of  silver,  argonin,  a  compound  of  silver  with 
casein,  and  argentamine,  ethylenediamine  silver  phosphate,  exert  a 
more  penetrating  action. 

In  man  systemic  poisoning  as  a  result  of  the  absorption  of  silver  does 
not  occur,  but  after  the  long-continued  use  of  silver  compounds  a  peculiar 
grayish  discoloration  of  the  skin  and  of  various  internal  organs  results  from 
the  deposition  in  these  tissues  of  insoluble  metallic  silver,  a  condition  to 
which  the  name  of  argyria  is  given. 

The  essential  action  of  the  salts  of  copper,  zinc,  and  lead  is  that 
of  astringents  and  corrosives.  Aluminum  acetate  exerts  both 
astringent  and  antiseptic  actions,  and  has  once  more  come  into  use 
as  a  mild  antiseptic  in  the  treatment  of  wounds. 

ANTISEPTICS  BELONGING  TO  THE  AROMATIC  GROUP 

Numerous  aromatic  substances  which  are  sufficiently  soluble  in 
water  to  reach  the  cells,  and  sufficiently  soluble  in  lipoids  to  penetrate 
them  readily,  possess  antiseptic  and  disinfectant  properties,  but  in 
stronger  concentrations  they  kill  the  cells  of  the  tissues  and  when 
absorbed  are  typical  nerve  poisons.  Among  these  the  most  efficient 
are  the  various  phenols  and  their  ethers  (Laubenheimer) .  As  the 
aromatic  hydrocarbons  are  less  powerful  than  the  phenols,  benzol 
is  a  feebler  antiseptic  than  carbolic  acid,  toluol  than  the  creosols, 
naphthalin  than  the  naphthols,  etc.  This  is  probably  to  be  explained 
by  their  slighter  solubility  in  water.  The  toxicity  of  the  phenols  does 
not  increase  with  the  number  of  hydroxyl  groups,  the  bivalent  phenols, 
brenzcatechin,  hydroquinone,  and  resorcin,  being  less  toxic  than  car- 
bolic acid.  The  substitution  of  acid  radicals  for  hydroxyl  groups,  as 
also  the  introduction  of  acid  groups  in  any  position  in  aromatic 
molecules,  markedly  lessens  their  activity.  In  spite  of  this,  free 
aromatic  acids,  benzoic  acid,  salicylic  acid,  etc.,  are  antiseptic  and 
cytotoxic,  but  their  neutral  salts,  which  are  insoluble  in  the  lipoids 
and  which  consequently  are  unable  to  penetrate  cells  rapidly,  are  not. 

Fate  in  the  Body. — Inasmuch  as  in  the  organism  the  benzol  ring,  as  a 
rule,  remains  intact,  the  fate  of  the  aromatic  substances  in  the  organism  differs 
from  that  of  substances  of  the  aliphatic  series.  In  general,  the  aromatic  com- 
pounds, after  undergoing  oxidation  or  losing  some  of  their  radicals,  enter  into 
synthetic  combination  with  various  intermediary  metabolic  products  and  form 
non-toxic  substances.  Thus,  the  phenols  are  conjugated  in  the  liver  with  sul- 
phuric and  glycuronic  acids,  and  many  of  the  aromatic  acids  are  combined  in  the 
kidney  with  glycocoll,  the  halogen  substituted  benzols,  for  example,  combining 
with  glycocoll  and  forming  mercapturic  acids. 

PHENOL,  C6H5OH,  or  carbolic  acid,  is  the  type  for  the  whole 
group.  It  occurs  as  colorless  crystals,  with  a  characteristic  pene- 
trating odor,  which  on  exposure  to  air  turns  pink.  It  is  soluble  in  20 


AROMATIC  ANTISEPTICS  515 

parts  of  water  and  is  readily  soluble  in  the  lipoids,  so  that  it  readily 
penetrates  into  all  tissues.  In  concentrations  ranging  from  1-200 
to  1-30,  it  is  a  very  efficient  bactericide,  killing  most  bacteria,  but 
spores  are  extremely  resistant  to  it.  It  was  carbolic  acid  which 
was  used  by  Lister  when  he  introduced  the  antiseptic  method  into 
medicine,  and  in  the  antiseptic  era  it  played  a  far  more  important 
role  than  at  present,  for  it  has  in  large  part  been  replaced  by  similar 
antiseptics,  but  more  particularly  because  to-day  chemical  disin- 
fectants are  employed  only  to  a  limited  extent  in  the  treatment  of 
wounds. 

Local  Action. — Concentrated  solutions  of  carbolic  acid  are  power- 
fully corrosive,  and  when  applied  to  the  skin  cause  a  white  eschar, 
which  later  turns  red  and  then  brown,  and  which  is  finally  cast  off 
without  the  formation  of  pus.  Even  5  per  cent,  solutions  cause  burn- 
ing and  pain  and  later  local  anesthesia.  More  dilute  solutions  also 
can  irritate  the  skin  or  on  longer  contact  cause  necrosis.  Conse- 
quently, as  carbolic  acid  readily  penetrates  the  skin,  dressings 
moistened  with  2-3  per  cent,  carbolic  acid,  if  left  in  place  for  a  con- 
siderable time,  may  cause  dry  gangrene  of  the  fingers  and  toes. 

Toxicology. — This  drug  is  rapidly  absorbed  wherever  applied, 
even  through  the  skin,  and  its  systemic  action  is  exerted  chiefly  on 
the  central  nervous  system.  In  animals  poisoned  by  it,  at  the  start 
symptoms  of  excitation  of  the  medullary  and  spinal  centres  pre- 
ponderate, but  in  man,  when  poisonous  amounts  are  absorbed,  paraly- 
sis of  the  central  nervous  system  occurs,  usually  without  preceding 
convulsions.  As  even  1  to  2  gm.  can  produce  poisoning  and  as  3  to  10 
gm.  are  usually  fatal,  the  maximal  dose  for  internal  administration 
should  be  0.1  gm. 

Poisoning  with  carbolic  acid  usually  occurs  as  a  result  of  suicidal 
attempts  or  of  mistaking  liquefied  carbolic  acid  for  more  dilute  solu- 
tions.* When  concentrated  solutions  or  the  pure  acid  are  swallowed, 
corrosion  of  the  mucous  membranes  like  that  produced  by  concentrated 
mineral  acids  results,  but  in  addition,  because  of  the  extreme  rapidity 
with  which  absorption  occurs,  the  local  symptoms  are  quickly  ob- 
scured by  those  of  the  systemic  poisoning  and  very  quickly,  usually 
after  a  few  minutes,  the  patient  becomes  completely  unconscious  and 
falls  into  a  state  of  profound  collapse. 

When  absorbed  from  the  rectum  or  from  the  uterus,  as  may  occur 
with  its  careless  use  post-partum,  even  relatively  small  amounts  of 
carbolic  acid  may  produce  severe  systemic  poisoning,  for  in  these 
cases  the  poison  passes  directly  into  the  general  circulation  without 
first  going  through  the  liver.  For  the  same  reason,  carbolic  acid  is 
distinctly  more  toxic  when  absorbed  through  the  skin. 

In  former  times,  when  carbolic  acid  was  much  more  widely  used 
in  surgery,  less  acute  carbolic  acid  poisoning1  was  frequently  ob- 


Carbolic  acid  liquefied  by  the  addition  of  10  per  cent,  of  water. 


516          ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

served,  beginning  with  vertigo,  headache,  a  tipsy  stupor,  and  vomit- 
ing, and  in  more  serious  cases  frequently  causing  cold  sweats, 
cyanosis,  and  small  frequent  pulse,  with  collapse  and  marked  fall  of 
the  body  temperature. 

In  such  cases  the  process  of  distoxication  proves  inadequate,  although 
ordinarily  by  the  formation  of  conjugated  sulphuric  and  glycuronic  acids  the 
organism  can  render  even  considerable  amounts  of  carbolic  acid  harmless,  provided 
they  are  gradually  absorbed.  As  a  portion  of  the  carbolic  acid  is  oxidized  in  the 
organism  to  dioxybenzols  and  is  excreted  in  the  urine  chiefly  in  the  form  of 
hydroquinone-sulphuric  acid,  and  as  in  the  urine  this  substance  is  readily  trans- 
formed into  greenish-brown  to  black  oxidation  products,  the  urine,  when  car- 
bolic acid  has  been  absorbed  in  considerable  amounts,  gradually  acquires  a  dark 
color  on  standing  or  is  already  discolored  when  passed.  When  too  large  amounts 
have  been  absorbed,  both  carbolic  acid  and  the  dioxybenzols  are  excreted  without 
undergoing  conjugation,  and  may  cause  albuminuria  and  nephritis. 

Treatment  of  Carbolic  Acid  Poisoning. — When  the  poison  has 
been  taken  by  mouth,  the  most  important  indication  is  to  wash  out 
the  stomach  immediately,  and,  if  this  is  done  quickly  enough,  the 
corrosion  caused  by  the  poison — in  contradistinction  to  that  caused 
by  concentrated  acids,  alkalies,  etc. — may  heal  without  leaving  serious 
results.  [A  15-20  per  cent,  solution  of  alcohol  should,  whenever  pos- 
sible, be  used  in  washing  out  the  stomach  in  these  cases. — TR.] 

Saccharated  lime  has  also  been  recommended  as  an  antidote,  as  this 
forms  an  insoluble  calcium  carbolate.  Both  animal  experiments  and 
clinical  experience  have  demonstrated  the  futility  of  administering 
sodium  sulphate  with  the  idea  of  augmenting  the  synthesis  of  ethereal 
sulphuric  acid  and  thus  rendering  the  absorbed  phenol  non-toxic 
(Tauber,  Marfori). 

Sulphocarbolates. — If  carbolic  acid  be  dissolved  in  concentrated  sulphuric 
acid,  sulphocarbolic  acid  is  formed,  which  is  far  less  active  than  carbolic  acid 
itself.  The  iodized  parasulphocarbolic  acid  has  been  introduced  commercially 
under  the  name  of  sozoiodolic  acid,  and  has  been  used  in  the  form  of  its  zinc  salt 
in  the  treatment  of  gonorrhoea  and  in  the  form  of  its  mercurial  salt  in  the  treat- 
ment of  lues.  However,  in  all  probability  these  compounds  possess  no  advantage 
over  other  zinc  and  mercury  salts. 

THE  CBESOLS. — Next  to  carbolic  acid  the  cresols  are  the  most 
important  aromatic  disinfectants.  For  a  long  time  it  has  been  the 
custom  to  use  for  disinfection  on  a  large  scale,  in  place  of  the  ex- 
pensive pure  carbolic  acid,  the  cheaper  raw  acid  which  remains  after 
pure  carbolic  acid  has  been  extracted  from  coal-tar.  In  addition 
to  other  products  obtained  from  coal-tar  by  dry  distillation,  such 
as  naphthaline,  pyridine,  etc.,  this  raw  carbolic  acid  contains  three 
ieomeric  cresols,  homologues  of  phenol,  in  which  a  methyl  radical  re- 
places a  hydrogen  atom  in  the  ortho-,  meta-,  and  para-positions. 

OH 
,CH3 


CI 

Orthocresol  Metaoresol  Paracresol 


AROMATIC  ANTISEPTICS  517 

The  powerful  disinfectant  action  of  these  cresols  was  quickly 
recognized,  but  their  insolubility  rendered  their  utilization  as  disin- 
fectants difficult.  An  impure  mixture  of  these  three  isomers  is  known 
as  crude  cresol  or  tricresol,  while  creolin  is  an  emulsion  of  cresols  and 
hydrocarbons  of  uncertain  and  varying  composition.  In  the  form 
of  solutions  of  their  alkaline  soaps,  the  cresols  have  been  widely 
used,  lysol  and  the  liquor  cresolis  compositus  being  such  solutions 
which  contain  about  50  per  cent,  of  cresol.  Many  similar  prepara- 
tions may  be  obtained  under  different  names.  For  gross  disinfection 
quite  extensive  use  has  been  made  of  saprol,  which  is  a  mixture  of 
80  parts  of  crude  carbolic  acid  and  20  parts  of  petroleum,  and  which, 
because  of  the  presence  of  the  lighter  hydrocarbons,  floats  on  the 
materials  to  be  disinfected  and  covers  them  over  with  a  thin  coat- 
ing, from  which  the  cresols,  etc.,  gradually  permeate  the  whole 
mixture. 

Formerly  it  was  thought  that  these  cresols  were  less  toxic  than 
carbolic  acid,  but,  as  a  matter  of  fact,  when  absorbed,  they  are  by 
no  means  less  toxic.  Among  themselves,  however,  they  are  not  equally 
toxic,  metacresol  being  the  weakest,  and  paracresol  for  many  species 
of  animals  almost  twice  as  toxic,  while  orthocresol  lies  between 
(Wandel,  T aliens).  "While  the  cresols  are  more  powerfully  antiseptic 
than  phenol,  it  is  practically  of  greater  importance  that,  on  account 
of  their  slighter  absorbability,  they  are,  in  proportion  to  their  dis- 
infecting power,  relatively  less  toxic. 

When  absorbed,  the  cresols  produce  the  same  toxic  systemic  ef- 
fects as  carbolic  acid  (Kochmann).  Suicide  by  swallowing  lysol  has 
been  particularly  common  in  recent  years,  and  causes  the  same  un- 
consciousness and  collapse  as  does  carbolic  acid,  the  only  difference 
being  that  in  these  cases  convulsions  appear  to  occur  more  frequently 
than  in  carbolic  acid  poisoning.  The  treatment  of  such  poisoning 
is  the  same  as  that  of  carbolic  acid  poisoning. 

In  cresol  poisoning  also,  the  urine  becomes  dark  colored  (Matter),  and 
nephritis  occurs.  The  cresols  are  excreted  with  the  bile  (Wandel,  Bial),  and 
may  cause  parenchymatous  hepatitis. 

THYMOL. — Of  the  higher  homologues  of  phenol,  thymol,  methyl- 
isopropylphenol,  is  a  more  powerful  antiseptic  than  carbolic  acid  or 
the  cresols.  It  is  very  insoluble  in  water — 1  to  1000 — and  is  con- 
sequently absorbed  with  difficulty,  and  may,  therefore,  be  used  as  a 
relatively  non-toxic  antiseptic  wash. 

Of  the  dioxybenzols,  resorcin,  metadioxybenzol,  is  used  in  the 
treatment  of  diseases  of  the  skin  and  as  an  antiseptic  wash  and  has 
also  been  used  internally. 

PYROGALLOL,  or  pyrogallic  acid,  trioxybenzol,  is  a  powerful  reduc- 
ing agent  which  is  used  in  the  treatment  of  psoriasis  and  other 
parasitic  diseases.  It  is  very  irritant  or  even  corrosive  and  stains 
the  skin  black,  and,  as  it  is  also  readily  absorbed,  is  a  powerful  poison 
to  the  blood,  reducing  oxyhasmoglobin  to  methgemoglobin. 


518  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

In  the  treatment  of  skin  diseases,  use  is  also  made  of  chrysarobin, 
naphthaline,  and  beta-naphthol,  as  also  of  the  various  tars  obtained 
by  the  distillation  of  wood,  such  as  pix  liquida,  which  contains  phenol 
and  various  other  esters,  and  also  terpenes  and  resinous  acids,  or  the 
purified  tar,  anthrasol. 

Ichthyol,  a  vile-smelling  mixture  containing  10  per  cent,  of  sul- 
phur, which  is  obtained  by  the  distillation  of  bituminous  rocks  from 
the  Tyrol  containing  fossil  fishes,  is  used  for  similar  purposes. 

BALSAM  OP  PERU  is  an  antiseptic  agent  which  irritates  the  tissues 
but  slightly.  It  occurs  as  a  thick  brown  liquid,  and  is  a  mixture  of 
40-60  per  cent,  of  the  benzylester  of  cinnamic  acid,  10  per  cent,  of 
free  cinnamic  acid,  and  various  resins.  Even  this  relatively  non- 
toxic  antiseptic,  however,  when  absorbed  in  considerable  quantities, 
like  all  the  above-mentioned  antiseptics,  can  and  does  cause  damage 
to  the  kidneys.* 

Finally,  salicylic  acid  (ortho-oxybenzoic  acid)  is  a  powerful  anti- 
septic, hardly  exceeded  in  its  activity  by  phenol,  which,  however,  is 
almost  insoluble  in  water.  On  the  skin  it  exerts  a  keratolytic  and  an- 
tisudorific  action,  and  on  mucous  membranes  it  is  irritant  or  cor- 
rosive. Its  salts  are  only  feebly  antiseptic  and  are  not  corrosive.  For 
its  employment  as  an  internal  disinfectant  see  page  530. 

BIBLIOGRAPHY 

Bial:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56,  p.  416. 
Kochmann:  Arch,  intern,  de  Pharmacodyn.,  1905,  vol.  14,  p.  401. 
Laubenheimer :  Phenol  and  s.  derivate,  Wien  and  Berlin,  1909. 
Marfori:  Archive  di  Farmacol.  e  Terapia,  1894,  vol.  2. 
Matter:  Hofmeister's  Beitrage  zur  chem.  Physiol.,  1907,  vol.  10,  p.  251. 
Tauber:  Arch.  f.  exp.  Path.  u.  Pharm.,  1895,  vol.  36,  p.  197. 
Tollens:  Arch.  f.  exp.  Path.  u.  Pharm.,  1905,  vol.  52,  p.  220. 
Wandel:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56,  p.  161. 

IODOPORM. — While  the  treatment  of  wounds  by  antiseptic  solu- 
tions has  constantly  gone  more  and  more  out  of  fashion,  iodoform 
is  still  widely  used  as  an  antiseptic  dusting  powder,  although  much 
less  freely  than  formerly.  Its  value  lies  in  the  fact  that  it  is  very 
insoluble,  and  consequently,  without  causing  damage  to  the  tissues, 
remains  as  a  harmless  reserve  store  from  which  an  actually  effective 
substance  or  substances  are  gradually  split  off  under  the  influence  of 
the  secretions  of  the  wound.  It  occurs  as  a  yellow  crystalline  powder, 
with  a  characteristic  disagreeable  and  penetrating  odor,  and  is 
almost  insoluble  in  water,  but  readily  soluble  in  fats  and  ether.  It  is 
much  used  in  the  treatment  of  purulent  sinuses  and  ulcers,  and  with 
particularly  good  effect  in  tubercular  conditions.  In  vitro  it  is  very 
feebly  bactericidal,  even  tubercle  bacilli,  like  most  other  bacteria,  being 
unaffected  even  when  exposed  for  weeks  to  iodoform  vapor.  On  the 

*  [A  temporary  albuminuria  of  considerable  severity  often  follows  the  ex- 
ternal application  of  balsam  of  peru  in  the  treatment  of  scabies. — TR.] 


IODOFORM 


519 


jther  hand,  cholera  vibriones  are  relatively  quickly  killed  by  it 
(Baumgarten,  Troje  u.  Panke).  On  the  surface  of  wounds  it  gradu- 
ally goes  into  solution,  and  from  this  solution  iodine  is  slowly  and 
continually  liberated,  exerting  an  antiseptic  and  deodorizing  action 

the  wound  secretions.  As  iodine  is  chemically  extremely  active, 
it  acts  upon  all  the  chemical  labile  organic  substances  present  in  the 
secretions  of  the  wound,  and  in  this  fashion  destroys  putrefactive 
substances  and  probably  also  renders  various  toxins  harmless  * 
(Behring).  This  mild  iodine  action,  resulting  from  its  slow  liberation, 
also  acts  as  a  mild  stimulant  for  the  formation  of  granulations  in 
tubercular  lesions,  etc. 

Toxicology  of  lodoform. — The  iodine  liberated  from  iodoform  is 
absorbed  partly  as  an  albuminate,  or  in  the  form  of  other  organic 
compounds,  and  in  part  as  iodides  of  the  alkalies,  and  is  excreted 
in  the  urine  in  part  as  inorganic  iodides  and  in  part  in  organic 
combinations  of  still  unknown  nature.  Consequently,  iodoform,  like 
the  alkaline  iodides,  may  cause  general  iodine  effects,  such  as  coryza 
and  acne  (see  p.  400).  However,  iodoform  is  also  absorbed  un- 
changed, for  the  acute  iodoform  poisoning,  occurring  when  it  is  ab- 
sorbed in  too  large  amounts,  differs  very  essentially  from  the  toxic 
effects  produced  by  inorganic  iodine  compounds.  Such  poisoning 
develops  slowly,  the  first  symptoms  noted  being  those  of  vague  dis- 
turbances of  the  central  nervous  system,  which  are  followed,  after 
several  days,- by  conditions  of  mental  excitement,  hallucinations,  and 
delirium,  alternating  with  confusion  and  stupor,  but  in  some  cases 
the  poisoning  resembles  a  pure  narcosis.  These  symptoms  of  poison- 
ing are  due  to  the  absorption  of  iodoform  in  a  form  which  is  neuro- 
tropic,  Loeb  having  been  able  to  find  iodine  in  the  brain  after  the 
administration  of  iodoform  and  other  lipoid  soluble  organic  iodine 
compounds,  although  even  after  the  administration  of  large  quan- 
tities of  organic  iodides  no  iodine  could  be  found  there.  When 
absorbed  by  the  cells  of  the  brain,  iodoform  acts  as  a  narcotic  in  the 
ime  fashion  as  other  lipoid  soluble  indifferent  substances;  but, 
as  its  absorption  into,  and  particularly  its  elimination  from,  the  brain 
occurs  much  more  slowly  than  does  that  of  the  closely  related  chloro- 
form, its  action  often  lasts  for  days  or  weeks.  In  such  cases,  just 
as  after  chloroform,  fatty  degeneration  of  parenchymatous  organs 
)ccurs. 

The  treatment  for  iodoform  poisoning  can  consist  only  in  its 
imediate  removal  from  the  situation  from  which  it  is  being  ab- 
sorbed. However,  owing  to  the  firmness  with  which  it  is  combined 
ath  the  nerve-cells,  the  unfavorable  course  of  the  poisoning  cannot 
always  be  prevented  by  such  measures. 

IODOFORM  SUBSTITUTES. — The  extremely  disagreeable  odor  of  iodoform  has 
led  to  the  introduction  of  numerous  substitutes,  chiefly  iodized  aromatic  corn- 
According  to  Heile,  under  these  conditions  other  soluble  decomposition 
products  containing  iodine  are  formed,  which  produce  an  antiseptic  effect. 


520          ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

pounds  which  are  themselves  antiseptic  and  which  are  also  supposed  to  liberate 
iodine  in  the  tissues,  but  none  of  these  substitutes  has  proven  equally  efficient 
with  iodoform.  It  appears  that  benzol  derivatives,  such  as  Loretin  (iodoxy- 
quinolinesulphonic  acid),  Nosophen  (tetraiodophenolphthalein),  Losophan  (tri- 
iododimetacresol ) ,  Sozoiodol  ( iodoparaphenolsulphonic  acid),  etc.,  in  which  the 
iodine  is  combined  directly  with  the  benzol  ring,  do  not  liberate  iodine  in  the 
organism  and  consequently  act  only  as  aromatic  disinfectants.  On  the  other  hand, 
similar  pyrrol  derivatives,  such  as  lodol  (tetraiodopyrrol),  do  liberate  iodine, 
Recently  Isoform  (paraiodoanisol),  has  appeared  to  be  of  value.  Of  the  benzol 
derivatives  in  which  iodine  is  present  in  a  side  chain,  Aristol  (dithymoldi iodide) 
and  Europhen  (diisobutylorthocresol iodide)  may  be  mentioned. 

Bismuth  preparations,  such  as  Xeroform  (tribromphenol-bismuth)  and  Airol 
( bismuth-oxyiodogallate ) ,  and  formaldehyde  compounds,  are  also  employed  for 
the  same  purpose  as  iodoform. 

BIBLIOGRAPHY 

Baumgarten:  Berl.  klin.  Woch.,  1887,  No.  20. 
Behring:  Deut.  med.  Woch.,  1887,  No.  20;  1888,  p.  653. 
Heile:  Arch.  f.  klin.  Chirurgie,  1903,  vol.  71,  p.  781. 
Loeb,  Oswald:  Arch.  f.  exp.  Path.  u.  Pharm.,  1907,  vol.  56. 
Troje  u.  Panke:  Berl.  klin.  Woch.,  1891,  No.  20. 

URINARY  ANTISEPTICS 

The  drugs  which  are  excreted  in  the  urine  in  an  antiseptically 
active  form  are  discussed  in  another  section  (see  p.  367). 

INTESTINAL  DISINFECTION 

Any  real  disinfection  of  the  intestines  is  impossible  of  attain- 
ment, and  in  fact  it  is  doubtful  whether  it  is  possible  by  pharma- 
cological agents  to  cause  even  an  inhibition  of  the  growth  of  the 
intestinal  flora.  It  must  be  remembered  in  this  connection,  however, 
that  great  difficulty  attends  the  demonstration  of  any  diminutioi 
of  the  growth  or  of  the  activity  of  intestinal  bacteria  (Stern}. 

Often  the  quantity  of  the  conjugated  aromatic  substances  of  the  urine  which 
are  formed  by  proteid  decomposition  in  the  intestine  has  been  used  as  a  measure 
of  the  amount  of  bacterial  fermentation  in  the  intestine;  but,  in  addition  to  the 
fact  that  this  factor  permits  an  estimation  only  of  the  intensity  of  proteid  putre- 
faction, and  not  of  the  activity  of  other  bacteria, — for  example,  those  fermenting 
carbohydrates, — the  quantity  of  these  aromatic  substances  excreted  in  the  urine 
depends  also  upon  the  extent  to  which  they  are  absorbed,  as  also  on  the  extent 
to  which  they  are  further  transformed  in  the  organism.  It  is,  therefore,  clear 
that  this  method  of  estimating  the  bacterial  activity  in  the  intestine  must  be 
very  unreliable.  The  attempt  has  also  been  made  to  determine  the  effects  of 
supposed  intestinal  disinfectants  by  determining  the  number  of  bacteria  in  the 
fseces  before  and  after  the  administration  of  such  drugs,  as  also  by  determining 
the  viability  of  non- pathogenic  foreign  bacteria  after  their  passage  through  the 
intestine.  These  methods  also  permit  conclusions  only  as  to  the  life  conditions 
for  the  bacteria  in  the  lowest  segments  of  the  intestines,  while  the  particularly 
important  thing  in  intestinal  disinfection  is  the  influencing  of  bacteria  in  the 
small  intestine.  For  these  various  reasons,  those  experiments  in  which  the  bac- 
teria were  counted  in  material  obtained  from  the  small  intestine  through  fistulae 
have  given  the  most  reliable  information.  [Even  such  investigations  have  indi- 
cated that  few,  or  none,  of  the  so-called  intestinal  antiseptics  exert  any  appre- 
ciable effect  on  the  intestinal  flora.  The  composition  of  the  diet  appears  to  be 
one  of  the  most  important  factors  in  determining  the  nature  or  types  of  the 
strains  predominating  in  the  intestine. — TB.] 

Only  those  substances  can  act  as  intestinal  disinfectants  which 
are  not  absorbed  completely  in  the  upper  portion  of  the  intestine 


ANTHELMINTICS  521 

and  which,  on  account  of  their  difficult  absorption,  are  relatively 
non-toxic.  One  of  the  most  widely  used  intestinal  antiseptics  is 
salol,  or  phenyl  salicylate,  which  is  rather  insoluble  and  is  decomposed 
in  the  intestine  into  its  two  antiseptic  components,  phenol  and 
salicylic  acid.  Salicylic  acid  itself,  as  also  napthaline,  beta  napthol, 
and  particularly  thymol,  have  been  stated  to  exert  more  or  less  dis- 
infectant action  in  the  intestine.  The  most  efficient  intestinal  disin- 
fectant, however,  is  calomel,  which  probably  owes  its  efficiency  more 
to  its  cathartic  action  than  to  the  fact  that  it  is  partially  transformed 
into  soluble  mercury  compounds  which  possess  antiseptic  powers. 
[This  is  very  doubtful.  See  Harris. — TR.] 

BIBLIOGRAPHY 

Harris:  J.  of  A.  M.  A.,  1912. 

Stern :  Ztschr.  f .  Hygiene  u.  Infekt.,  1892,  vol.  12,  p.  88. 

ANTHELMINTICS 

Anthelmintics,  or  vermifuges,  are  drugs  used  to  expel  intestinal 
animal  parasites,  such  as  the  various  tapeworms,  Taenia  solium,  T. 
mediocanellata,  Bothriocephalus  latus,  round  worms  or  Ascaris 
lumbricoides,  Oxyuris  vermicularis,  and  the  hook-worm,  Ankylostoma 
duodenal  or  Uncinaria  americana.  They  are  all  substances  the  value 
of  which  has  been  discovered  empirically,  and  which  possess  the 
property  of  reaching  the  lower  portion  of  the  intestine  without  being 
absorbed  to  any  great  extent.  Their  toxic  action  is  by  no  means 
specific,  for,  being  absorbed  with  difficulty,  they  come  in  contact 
with  the  parasites  in  the  intestines  in  much  stronger  concentrations 
than  reach  the  tissue  cells  of  the  host  when  they  are  absorbed.  If 
they  are  absorbed  in  large  amounts,  they  are  all  toxic  in  the  host 
also. 

These  anthelmintics  do  not  always  kill  the  parasites,  but  only 
benumb  them,  so  that  the  worms  are  no  longer  able  to  hold  fast 
to  the  mucous  membrane  by  their  suckers,  and  consequently  may 
be  readily  evacuated  with  the  general  intestinal  contents.  For  this 
reason,  in  case  the  vermifuge  itself  does  not  produce  catharsis,  a 
cathartic  should  be  administered  some  time  after  the  vermifuge,  in 
order  that  both  the  parasites  and  the  unabsorbed  portion  of  the  toxic 
drug  may  be  expelled  from  the  intestine. 

As  a  preliminary  preparation  in  the  treatment,  it  is  advantageous  to  empty 
the  intestine  by  a  mildly  acting  laxative  in  order  that  the  action  of  the  drug  on 
the  parasite  will  not  be  interfered  with  by  the  presence  of  too  large  amounts  of 
material  in  the  intestine.  However,  it  is  a  mistake  to  empty  the  intestine  com- 
pletely by  too  long-continued  preliminary  fasting  or  purging,  for  this  increases 
the  danger  of  the  absorption  of  the  vermifuge  and  consequently  augments  the 
danger  of  poisoning. 

OLEORESINA  ASIPIDII,  obtained  from  the  rhizome  of  filix-mas,  or 
toale  fern,  is  a  dark  green  thick  oil,  with  a  very  disagreeable  taste, 


522  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

which    contains    a   number    of   active    principles    which   have    been 
isolated  in  pure  form  only  comparatively  recently  (Poulsson,  Bohm). 

These  are  non-nitrogenous  acids,  of  which  the  most  important  is  filicic 
acid,  or  filicin,  which  in  crystalline  form  is  inactive  but  occurs  in  the  fresh 
oleoresin  in  an  amorphous  active  form. 

Other  active  principles  are  flavaspidic  acid,  albaspidin,  and  aspidinol,  etc., 
and  also  an  amorphous  substance  named  filmaron  (Kraft).  In  other  ferns 
very  similar  substances  occur,  which,  like  those  named  above,  are  all  compounds 
of  butyric  or  isobutyric  acid  with  phloroglucin  and  its  homologues. 

These  active  principles  are  both  neurotoxic  and  myotoxic  poisons. 
In  invertebrates  Straub  has  found  that  filicic  acid  is  very  toxic  to 
smooth  muscle,  and  it  is  probable  that  the  medicinal  activity  of  male 
fern  is  dependent  on  its  power  of  paralyzing  the  muscles  of  the 
different  tasnia. 

In  mammals  filicic  acid  causes  excitation  of  the  central  nervous 
system,  evidenced  by  twitching  of  the  muscles  and  often  by  tetanic 
convulsions,  and  finally  it  causes  paralysis  of  the  muscles,  heart- 
failure,  and  collapse.  In  man  also  poisoning  has  often  been  observed 
after  too  large  doses  or  improper  administration  of  this  drug.  Under 
these  conditions  the  first  symptoms  are  due  to  gastro-intestinal  irrita- 
tion, which  causes  nausea,  vomiting,  and  purging,  later  stupor  and 
faintness  or  even  convulsions  may  develop,  while  cardiac  weakness, 
disturbances  of  respiration,  and  temporary  impairment  of  the  vision, 
or  even  permanent  blindness  due  to  optic  atrophy,  may  also  result 
from  its  administration.  Most  of  the  cases  of  poisoning  recorded  have 
been  the  result  of  exceeding  the  admissible  dose  (see  below),  which  at 
the  highest  should  not  be  larger  than  8-10  gm.  of  the  oleoresin,  or  have 
resulted  from  the  repetition  of  an  unsuccessful  treatment  on  the  follow- 
ing day.  [Many  American  authors  unite  in  recommending  that  the 
maximum  dose  should  not  exceed  6.0  gm. — TR.] 

In  the  usual  doses,  not  exceeding  8.0  gm.,  male  fern  in  almost  all 
cases  is  well  borne  if  administered  on  a  not  entirely  empty  stomach 
and  if,  one  or  two  hours  after  its  administration,  calomel,  senna,  or 
other  efficient  cathartic  be  administered,  so  as  to  bring  about  a  thorough 
removal  of  the  drug.  [Castor  oil  should  not  be  used  as  a  cathartic  in 
these  cases,  for  the  literature  shows  that  many  of  the  cases  of  poisoning 
have  been  those  in  which  this  drug,  which  is  a  solvent  for  the  poisonous 
active  principles,  has  been  administered. — TR.]  The  relative  non-tox- 
icidity  of  filicic  acid  for  the  host  is  due  in  part  to  the  destruction  of  this 
drug  in  the  organism  of  the  higher  animals  (Straub). 

Kousso,  OR  KOOSSO,  the  dried  female  flowers  of  Hagenia  abyssinica, 
long  used  as  a  taenicide,  contains  substances  which,  like  the  active  con- 
stituents of  the  various  ferns,  are  compounds  of  butyric  acid  with 
members  of  the  phloroglucin  series,  the  most  important  being  the 
amorphous  koussotoxin  (Lobbeck).  In  the  lower  animals  this  too  is 
a  powerful  muscle  poison,  resembling  filicic  acid.  From  15.0  to  25.0 
gm.  of  the  crude  drug  in  the  form  of  a  decoction  acts  as  an  efficient 


ANTHELMINTICS  523 

vermifuge,  usually  without  causing  serious  symptoms.  However,  only 
the  fresh  blossoms  are  reliable  in  their  action. 

KAMALA,  the  glands  and  hairs  of  the  capsules  of  Mallotus  philip- 
pinensis  or  Rottlera  tinctoria,  occurs  as  a  granular  brick-red  powder, 
odorless  and  nearly  tasteless,  and  in  the  dosage  of  6.0-12.0  gm.  is 
employed  as  a  mildly  acting  vermifuge.  As  this  drug  itself  exerts 
a  cathartic  action,  it  need  not  be  followed  by  a  laxative.  Its  active 
constituent,  the  resinous  rottlerin,  is  also  a  phloroglucin  derivative. 

PELLETIERINE. — The  active  constituents  of  granatum,  the  bark  of 
Punica  granatum,  and  of  the  betel  or  areca  nut,  are  all  alkaloids. 
Granatum  contains,  in  addition  to  very  considerable  amounts  of  tan- 
nic  acid,  a  number  of  alkaloids  of  which  pelletierine  and  isopelletierine 
are  very  toxic  to  the  various  tapeworms.  [The  pelletierine  of  com- 
merce is  a  mixture  of  various  alkaloids. — TR.]  Doses  of  0.3—0.4  gm. 
pelletierine  sulphate  or  tannate  usually  act  as  efficient  taenicides  with- 
out causing  severe  symptoms  of  poisoning.  They  are  best  admin- 
istered together  with  0.5-1.0  gm.  of  tannic  acid,  in  order  that  the 
alkaloid  may  be  retained  in  the  intestine  in  the  form  of  its  rather 
insoluble  tannate.  The  symptoms  of  poisoning,  when  this  occurs, 
consist  of  dizziness,  faintness,  and  weakness,  and  occasionally  serious 
disturbances  of  vision.  The  crude  drug  is  of  uncertain  activity  ex- 
cept when  fresh,  and,  as  from  50  to  60  gm.  must  be  taken  within 
an  hour,  the  large  amount  of  tannic  acid  contained  in  it  (sometimes 
as  much  as  22  per  cent.)  is  a  great  disadvantage  in  connection  with 
its  use,  as  it  may  cause  nausea  and  vomiting.  The  tannin  can,  how- 
ever, be  removed  from  the  decoction  by  treating  it  with  chalk  or 
milk  of  lime. 

On  the  higher  animals  pelletierine  is  a  central  nervous  excitant 
(v.  Schroder)  and,  in  addition,  exerts  an  action  on  the  muscles  similar  to  that 
of  veratrine.  Its  relatively  great  toxicity  on  tapeworms  is  probably  dependent 
on  this  action  on  the  muscles. 

Betel  or  area  nuts  are  used,  particularly  in  veterinary  practice,  as  tseni- 
cides.  Arecolin,  the  alkaloid  contained  in  them,  belongs,  according  to  its  pharma- 
cological actions,  in  the  muscarine  and  pilocarpine  group  (see  pp.  153  and  372). 
On  account  of  the  readiness  with  which  it  is  absorbed,  this  drug  is  too  dangerous 
to  be  used  as  a  tenicide. 

SANTONIN,  the  active  principle  of  santonica,  or  levant  wormseed, 
which  is  the  only  drug  used  to  expel  the  round  worm,  Ascaris  lumbri- 
coides,  is  an  acid  anhydride.  According  to  v.  Schroder,  santonin  does 
not  kill  these  worms,  but  only  drives  them  down  into  the  large  in- 
testine, from  which  they  may  be  readily  removed  by  a  cathartic. 
It  is  absorbed  with  extreme  difficulty,  and  is  consequently  to  a  large 
extent  excreted  in  the  faeces,  but  a  certain  portion  may  be  absorbed 
and  cause  poisoning. 

Pharmacologically  it  is  a  eonvulsant,  which  in  animals  causes 
epileptiform  convulsions,  marked  depression  of  the  temperature,  and 
death.  In  man  also  its  use  has  been  observed  to  cause  not  only 


084 

nausea,  vomiting,  and  purging,  but  also  convulsions.  It  frequently, 
even  in  moderate  doses,  causes  a  very  marked  effect  on  the  vision,  as 
a  result  of  which,  objects  appear  to  be  first  violet  in  color  and  later 
yellow.  This  effect  is  known  as  xanthopsia.  Disturbances  of  the 
senses  of  smell  and  taste  may  also  occur.  The  urine  contains  a  trans- 
formation product  of  santonin,  santogenin  (Jaffe),  which  in  alkaline 
reaction  colors  the  urine  cherry-red.  The  dose  of  santonin  ranges 
from  0.02  gm.  up  to  the  maximum  dose  of  0.1  gm.  [Forcheimer  states 
that  he  has  seen  death  follow  a  dose  of  santonin  in  a  child  to  whom  it 
had  been  given  on  a  suspicion  of  the  presence  of  worms,  although  in 
reality  this  was  not  the  case.  He  also  states  that  0.13  gm.  has  caused 
death  in  a  child. — TR.] 

THYMOL. — In  the  treatment  of  hook-worms,  thymol  is  the  drug 
par  excellence.  This  occurs  as  large  colorless  crystals  possessing  an 
aromatic  odor  and  pungent  taste.  [It  is  soluble  in  1200  parts  of 
water  and  in  one  part  of  alcohol,  and  fairly  soluble  in  fats  and  oils 
and  in  alkaline  solutions.  Extensive  experience  in  the  treatment  of 
this  disease  has  shown  thymol  to  be,  when  properly  administered,  a 
very  certain  means  of  causing  the  expulsion  of  these  parasites,  and 
that  its  use  is  unattended  with  danger  if  it  be  administered  with  the 
observance  of  certain  simple  and  necessary  precautions. 

The  dose  should  not  exceed  4.0  gm.,  best  administered  in  capsules 
containing  about  0.5-0.7  gm.  in  finely  divided  form  and  triturated 
with  milk-sugar.  These  should  be  taken  on  an  empty  stomach,  and 
followed  in  from  one  to  two  hours  by  a  promptly  acting  cathartic, 
preferably  magnesium  or  sodium  sulphate.  For  twelve  hours  before 
its  administration  and  following  its  administration  until  the  bowels 
have  moved  thoroughly,  no  fatty  or  oily  food,  or  alcohol,  should  be 
taken.  Stiles  states  that  he  has  known  of  fatal  results  due  to  the 
administration  of  castor  oil  as  a  purgative  following  the  thymol. — TR.  ] 
One  death,  following  the  administration  of  6  gm.  to  an  anaemic  indi- 
vidual, warns  against  its  indiscriminate  or  careless  use.  [As  a  rule, 
only  comparatively  slight  systemic  symptoms  should  occur,  and  in 
fact  with  precautions  even  these  occur  but  seldom.  Its  toxic  action 
closely  resembles  that  of  carbolic  acid. — TR.] 

BIBLIOGRAPHY 

B5hm:  Arch.  f.  exp.  Path.  u.  Pharm.,  1897,  vol.  38,  p.  35. 
Bohm:  Annalen  der  Chemie,  1902,  vol.  318,  p.  230. 

Forcheimer:  Prophylaxis  and  Treatment  of  Internal  Disease,  2nd  ed.,  p.  186. 
Jaffe:  Ztschr.  f.  physiol.  Chemie,  1897,  vol.  22. 
Kraft:  Arch.  d.  Pharmacie,  1904. 
Lobbeck:  Arch.  d.  Pharm.,  1901,  vol.  239. 
Poulsson:  Arch.  f.  exp.  Path.  u.  Pharm.,  1891,  vol.  29. 
Semper:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  10. 
Straub:  Arch.  f.  exp.  Path.  u.  Pharm.,  1902,  vol.  48. 

v.  Schroder,  W.:  Arch.  f.  exp.  Path.  u.  Pharm.,  1884,  vol.  18,  p.  381;  1885,  vol.  19, 
p.  304. 


SPECIFIC  DISINFECTANTS  525 

SPECIFIC  DISINFECTANTS 

The  general  antiseptics  kill  the  protoplasm  of  all  microbes  as  also 
that  of  the  tissue  cells.  However,  there  are  very  distinct  differences 
in  the  susceptibility  of  the  different  pathogenic  and  non-pathogenic 
varieties  to  the  different  antiseptics.  This  higher  susceptibility  of 
certain  types  forms,  as  it  were,  a  bridge  to  the  outspoken  specific 
relationship  between  certain  pathogenic  organisms  and  certain  cell 
poisons,  on  which  depends  the  possibility  of  killing  such  parasites, 
even  in  the  tissues  of  the  host,  without  harming  him. 

AVhere  such  specific  relationships  do  not  exist,  an  internal  dis- 
infection is  from  its  very  nature  impossible.  Even  in  mucous  mem- 
branes and  wounds,  general  cell  poisons  cannot  produce  disinfection 
without  severely  damaging  the  tissue  cells,  and  consequently  it  is 
absolutely  impossible  to  utilize  such  general  cell  poisons  as  means 
of  attacking  the  micro-organisms  in  the  blood  and  in  the  interior  of 
the  tissues,  because,  on  the  one  hand,  the  greater  susceptibility  of  the 
central  nervous  system  from  the  start  prevents  the  use  of  higher 
concentrations,  while,  on  the  other,  even  those  concentrations  which 
are  effective  on  the  surface  of  wounds  are  not  effective  in  the  blood 
and  in  the  tissues,  for  the  disinfectant  is  diverted  from  the  pathogenic 
organisms  by  the  constituents  of  the  body  to  a  much  greater  extent 
when  it  is  present  in  the  general  circulation  than  is  the  case  in 
the  secretions  of  wounds. 

A  striking  example  of  the  disproportion  between  disinfectant  power  in  the 
reagent  glass  and  in  the  organism  has  been  furnished  by  the  observations  of 
Bechhold  and  Ehrlich,  who  discovered  in  tetrabrom-o-kresol  and  in  hexabrom- 
dioxy-diphenylcarbinol  two  substances  possessing  extraordinary  disinfecting  power 
outside  of  the  body  and  relatively  slight  toxicity.  It  was  consequently  possible 
to  introduce  these  antiseptics  into  the  bodies  of  animals  in  doses  less  than  one- 
one-hundredth  part  of  which  would  have  been  sufficient  to  prevent  the  further 
development  of  pathogenic  bacteria  (diphtheria)  if  they  had  been  as  effective 
in  corpore  as  in  vitro.  However,  these  drugs  failed  entirely  to  cause  an  internal 
disinfection.  This  is  explained  by  the  fact  that  even  blood-serum  markedly  less- 
ened their  disinfectant  power,  and  in  the  body  it  is  evident  that  the  conditions 
were  still  more  unfavorable  for  the  absorption  of  the  disinfectants  by  the 
bacteria. 

This  explains  why,  except  in  the  case  of  specific  drugs,  internal 
disinfection  fails,  as  does,  for  example,  intravenous  injection  of  cor- 
rosive sublimate  which  has  been  tried  in  various  diseases  of  the  lower 
animals.  On  the  other  hand,  it  is  easy  to  understand  why  the  at- 
tempts to  obtain  an  internal  disinfection  have  never  been  abandoned, 
for  the  effects  of  quinine  in  malaria  and  of  mercury  in  syphilis  cer- 
tainly prove  that  such  specific  therapy  is  a  possibility.  Particularly 
against  tuberculosis,  specifics  are  constantly  being  recommended,  but, 
unfortunately,  only  after  insufficient  investigation. 

THE  CREOSOTE  TREATMENT  OF  TUBERCULOSIS  has  become  of  practical 
importance.  The  tar  obtained  from  beech  wood  is  one  of  the 
antiseptics  longest  known.  From  it  is  obtained,  by  distillation,  a 


526 

dark  yellow  fluid  with  a  smoky  odor  and  burning  taste — creosote. 
This  is  composed  chiefly  of  guaiacol,  the  methyl  ether  of  brenzcatechin, 
which,  in  pure  form,  occurs  as  colorless  crystals,  but  which,  as  ob- 
tained in  commerce,  is  usually  a  fluid  differing  from  creosote  chiefly 
in  its  less  disagreeable  odor.  Guaiacol  itself  is  a  powerful  antiseptic, 
but  whether  after  absorption  it  can  exert  this  action  or  whether  it 
circulates  in  the  blood  in  active  combinations  has  not  been  definitely 
determined.  It  is  excreted  in  the  urine  as  an  ethereal  sulphuric  acid. 

In  the  mouth  creosote  and  guaiacol  cause  burning  and,  when  taken 
in  concentrated  solution,  violent  irritation  of  the  mucous  membranes, 
with  vomiting  and  purging.  Although  guaiacol  resembles  the  related 
phenol  in  these  local  actions,  after  absorption  it  is  less  toxic.  "When 
rapidly  absorbed,  as  after  subcutaneous  administration,  it,  like  other 
aromatic  compounds,  lowers  the  temperature  [and  acts  as  an  an- 
algesic.— TR.] 

After  having  been  used  to  a  large  extent  in  France,  creosote  was 
introduced  into  Germany  especially  by  Sommerbrodt  in  1887,  but  was 
soon  replaced  by  the  purer  and  less  irritant  guaiacol.  Numerous 
clinical  observers  testify  to  the  fact  that,  when  administered  for  a 
considerable  period  in  increasing  doses,  up  to  one  gramme  per  diem, 
it  causes  improvement  of  the  appetite  and  nutrition,  with  gain  in 
weight,  and  also  exerts  a  favorable  influence  on  the  cough  and 
expectoration.  Perhaps  a  slight — quantitatively  hardly  measurable 
— amount  is  excreted  through  the  lungs. 

It  appears  to  be  impossible  that  without  causing  systemic  poisoning 
one  can  attain  a  concentration  of  guaiacol  on  the  blood  and  tissues 
which  will  suffice  to  kill  the  tubercle  bacilli  (Guttmann,  Cornet) 
and  even  an  inhibition  of  their  growth  by  such  means  appears 
improbable,  for,  like  other  phenols,  guaiacol  is  rapidly  transformed 
in  the  body  into  antiseptically  inactive  conjugated  sulphates.  In 
case  creosote  and  guaiacol  actually  do  exert  favorable  actions  in 
tuberculosis,  these  must  be  attributed  to  their  indirect  actions,  per- 
haps because,  like  bitters,  these  drugs  favorably  affect  the  digestion 
and  possibly  also  act  as  intestinal  antiseptics.  From  this  point  of  view 
it  appears  rational  to  attempt  only  a  mild  treatment  with  these 
drugs,  and  not  the  so-called  intensive  treatment,  in  which,  by  combin- 
ing with  their  internal  administration  their  administration  through 
the  skin  and  as  inhalations,  the  endeavor  is  made  to  attain  the  highest 
possible  saturation  of  the  organism  with  guaiacol.  Moreover,  it 
should  be  remembered  that  the  oral  administration  of  large  doses 
quite  often  causes  disturbances  of  the  digestion. 

It  is  for  this  reason  that  at  present  the  preference  is  given  to  the 
carbonates  of  creosote  and  guaiacol  (creosotal  and  duotal),  which  are 
insoluble  and  consequently  non-irritant  in  the  stomach,  but  which 
are  decomposed  gradually  in  the  intestine.  Of  similar  preparations 
mention  may  be  made  of  the  valerianate  of  creosote  (Eosot)  and  of 


QUININE  IN  MALARIA  527 


aiaeol  (Geosot),  potassium  guaiacol  sulphanate  (Thiokol),  a  powder, 
of  which  the  dose  is  from  2  to  5  gin.  daily,  and  its  solution,  Sirolin, 

BIBLIOGRAPHY 

Bechhold  u.  Ehrlich :   Ztschr.  f .  physiol.  Chemie,  1906,  vol.  47. 
Cornet:   Nothnagel's  Handbucli  d.  Path.  u.  Ther.,  vol.  14,  p.  536. 
Guttmann:  Ztschr.  f.  klin.  Med..  1888,  vol.  13. 

In  various  protozoal  diseases  it  has  been  definitely  shown  that 
drugs  may  produce  specific  etiotropic  actions,  for  quinine  kills 
malarial  parasites  and  certain  arsenical  compounds  can  kill  try- 
panosomes  and  the  Spirochaeta  pallida.  The  action  of  mercury  in 
syphilis  is  another  example  of  such  specificity,  and  it  is  in  the 
highest  degree  probable  that  salicylic  acid  also  is  an  etiotropic  cura- 
tive agent,  acting  on  the  still  unknown  cause  of  articular  rheumatism. 

QUININE  IN  MALARIA 

Through  its  action  on  heat  regulation  and  metabolism,  quinine  is 
an  antipyretic,  which  more  or  less  efficiently  controls  pyrexia  in 
various  infectious  diseases.  Its  almost  universally  curative  effect 
in  malaria  is,  however,  due  to  altogether  different  causes,  for  here 
all  the  symptoms  of  the  disease  and  not  the  fever  alone  are  controlled 
by  it.  Here  we  are  dealing  with  a  typical  example  of  specific  etio- 
trophic  therapy,  for  in  doses  which  are  harmless  to  man  quinine 
damages  and  destroys  most  of  the  forms  of  the  malarial  parasites 
in  the  blood. 

Up  to  the  eighth  decade  of  the  last  century  it  was  generally  as- 
sumed that  in  malaria  quinine  produced  its  effects  through  its  action 
on  the  nervous  system,  but  in  1867  Binz  demonstrated  the  great 
susceptibility  to  this  drug  exhibited  by  certain  simple  protoplasmic 
organisms,  and  based  on  this  the  hypothesis  that  quinine  cured 
malaria  by  acting  directly  on  its  cause,  which  probably  would  be 
found  to  be  one  of  the  lowest  forms  of  living  organisms.  He  further 
stated  that  quinine  was  much  less  toxic  to  the  healthy  cells  of  man 
than  to  this  hypothetical  cause  of  malaria. 

The  first  objects  used  by  Bins  in  these  investigations  were  parameciae, 
which  were  immediately  killed  by  a  one  to  four  hundred  solution,  and  whose 
movements  were  lessened  by  solutions  of  one  to  twenty  thousand  and  entirely 
stopped  after  two  hours,  although  these  same  infusoria  were  much  more  resistant 
to  other  alkaloids,  such  as  morphine,  strychnine,  santonin,  etc.  Binz  was  able 
to  demonstrate  the  same  striking  susceptibility  to  quinine  in  fresh-water  amoebia, 
and  also  in  the  leucocytes  of  the  blood,  which  in  dilutions  of  one  to  fifty  thousand 
cease  their  amoeboid  movements  and  undergo  gross  granular  degeneration.  On 
the  other  hand,  other  amoebia — for  example,  salt-water  euglena — are  much  more 
resistant.  Quinine  is  also  a  very  powerful  poison  for  various  bacteria.  From 
these  various  facts,  Binz  was  justified  in  concluding  that  this  drug  acted  as  a 
specific. 

The  proof  of  the  correctness  of  this  theory  of  the  manner  in 
which  quinine  acted  could  be  obtained  only  after  Laveran,  in  1880,  dis- 
covered and  recognized  the  Plasmodium  malariae  as  the  cause  of  this 


528          ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

disease,  and  after  this  discovery  had  been  confirmed  by  numerous  in- 
vestigators, when  it  was  found  that,  even  outside  the  body,  the  ad- 
dition of  quinine  solutions  to  the  blood  rapidly  kills  the  malarial 
organisms.  All  the  investigations  of  the  blood  in  malaria  have  shown 
that  during  the  administration  of  quinine  the  parasites  disappear 
from  the  blood,  and  that  they  may  be  recognized  as  persisting  there 
only  in  those  pernicious  cases  which  are  not  cured  by  quinine. 


FIG.  61. — Tertian  malarial  parasites:  a-e,  normal;/,  as  affected  by  quinine; 
g,  speculation  under  influence  of  quinine. 


In  malaria  the  paroxysms  of  fever  are  due  to  the  fact  that  the 
youngest  forms  of  the  sporozoa,  the  so-called  sporozoits,  which  have 
penetrated  into  the  red  blood-cells  and  developed  within  them,  after 
a  time  sporulate  and  leave  the  old  corpuscles  and  penetrate  into 
new  ones.  As  it  is  in  this  phase  of  their  life  history  that  quinine  is 
most  toxic  to  these  parasites,  when  given  some  hours  before  the  ex- 
pected paroxysm,  it  destroys  them  in  large  numbers  and  prevents 
the  next  paroxysm  or  moderates  its  severity  in  many  instances,  or  at 
least  prevents  its  recurrence.  Tertian  parasites  are  most  susceptible 
to  the  toxic  action  of  quinine,  the  quartan  ones  somewhat  less  so,  and 
least  of  all  those  of  the  pernicious  aestivo-autumnal  fever,  which  sporu- 
late -almost  entirely  in  the  internal  organs.  It  is  stated  that  quinine 
is  without  effect  on  the  gametes  of  the  severer  forms  of  malaria  whose 
sexual  cycle  occurs  only  in  anopheline  mosquitoes.  [This,  however, 
is  not  true,  for,  although  very  resistant  to  quinine,  the  persistent  ad- 
ministration of  large  doses  of  quinine  causes  the  disappearance  of  these 
parasites  from  the  blood,  at  any  rate  for  a  time,  or  at  the  least  causes 
a  marked  diminution  in  their  number  (see  van  Bezdorf). — TB.] 

Quinine  muriate  is  usually  administered  in  tertian  and  quartan 
malaria,  three  to  five  hours  before  the  expected  paroxysm,  in  doses  of 
0.3  to  0.7  gm.,  repeated  two  to  three  times  at  hourly  intervals,  and  its 
daily  administration  in  somewhat  smaller  doses  should  be  continued 
for  a  considerable  period  after  the  disappearance  of  active  malarial 
manifestations.  In  severe  cases  it  is  administered  several  times 
daily  in  doses  of  0.6-1.0  gm.  [In  refractory  or  pernicious  cases  it 
should  be  injected  intramuscularly,  for  which  purpose  the  very  solu- 


SALICYLIC  ACID  IN  RHEUMATISM  529 

ble  bimuriate  or  the  muriate  of  quinine  and  urea  are  the  most  suitable 
preparations. — TR.]  It  has  also  been  recommended  that  quinine  should 
be  given  in  broken  doses,  0.2  gm.  repeated  five  times  daily,  with  the  idea 
that  in  this  fashion  a  regular  and  continuous  absorption  will  occur 
and  that  a  persisting  action  in  the  blood  will  result. 

Quinine  is  slowly  absorbed  and  at  least  in  part  remains  in  the 
blood  in  an  unaltered  form,  for  one-fourth  to  one-third  of  the  amount 
administered  in  24  hours  is  excreted  unchanged  in  the  urine  (Giemsa 
u.  Schaumann,  Nishi) .  The  remainder  is  destroyed  in  the  organism. 
Its  relatively  slow  excretion  renders  it  possible  to  attain  with  permis- 
sible doses  a  constant  concentration  of  quinine  in  the  blood,  which 
endows  the  taker  with  a  certain  amount  of  prophylactic  protection 
against  the  sporozoits  which  may  be  introduced  by  mosquitoes.  In 
addition  to  the  symptoms  of  cinchonism  already  mentioned  (p.  477), 
large  doses  at  times  cause  hsematuria  or  haemoglobinuria,  and  it  is 
probable  that,  particularly  in  patients  severely  ill  with  malaria, 
quinine  causes  the  so-called  black-water  fever.  [The  evidence  for  and 
against  quinine  as  a  frequent  cause  of  haemoglobinuria  is  very  con- 
flicting, but  it  is  reasonably  certain  that,  while  quinine  is  not  respon- 
sible for  all  black-water  fever  occurring  in  malarial  patients,  it  is  often 
the  final  decisive  factor  in  its  production.  This,  however,  does  not 
constitute  a  contraindication  for  its  administration  in  any  cases  of 
malaria,  not  even  in  cases  with  black-water  fever,  so  long  as  the  para- 
sites may  be  found  in  the  blood. — TR.] 

BIBLIOGRAPHY 

Binz:  Zbl.  f.  med.  Wiss.,  1867,  p.  310. 

Binz:  Arch.  f.  mikrosk.  Anat.,  1867,  vol.  3,  p.  383. 

Giesma  u.  Schaumann:  Arch.  f.  Schiffs-  und  Tropenhyg.,  1907,  vol.  11. 

Nishi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  60,  p.  312. 

van  Bezdorf:   Southern  Med.  Jour.,  1913. 

SALICYLIC  ACID  IN  ACUTE  ARTICULAR  RHEUMATISM 
In  all  probability  the  action  of  salicylic  acid  in  this  disease  is  of  an 
etiotropic  nature,  although  this  cannot  be  certainly  maintained  inas- 
much as  the  pathogenic  organism  is  not  known.  Probably  the  causative 
agent  closely  resembles  streptococci  and  staphylococci,  and,  therefore, 
it  probably  is  not  of  protozoa!  nature.  Consequently,  this  drug  may 
be  looked  upon  as  one  of  the  group  of  general  bacterial  poisons  which 
possesses  specific  curative  properties.  As  these  bacterial  poisons  are 
at  the  same  time  general  cell  poisons,  and  as  salicylic  acid  is  by  no  means 
very  much  more  toxic  to  bacteria  in  general  than  it  is  to  the  suscep- 
tible tissues  of  the  host,  its  utility  as  an  internal  disinfectant  must 
depend  on  certain  special  conditions,  as  a  result  of  which  its  toxic 
action  on  the  central  nervous  system  may  be  avoided  while  it  may  still 
be  directed  against  the  causative  agent  of  rheumatism. 

Free  salcylic  acid  is  scarcely  less  toxic  to  bacteria  than  is  phenol, 
while  it  is  at  the  same  time  strongly  toxic  to  the  tissues.    On  the  other 
34 


530          ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

hand,  the  salicylate  of  soda  is  a  very  feeble  antiseptic  and  at  the  same 
time  very  slightly  toxic  to  the  tissues.  As  salicylic  acid  circulates 
in  the  blood  chiefly  or  entirely  in  the  form  of  its  sodium  salt,  it  is  evi- 
dent that  after  absorption  it  circulates  about  in  a  form  which  is  but 
slightly  toxic  for  the  patient's  tissues  but  at  the  same  time  also  but 
slightly  toxic  for  the  bacteria.  However,  as  shown  by  Binz,  a  rather 
high  carbon  dioxide  tension  sets  free  the  active  acid  from  the  salicy- 
lates. While  the  CO2  tension  of  normal  tissues  (about  6  per  cent.)  is 
not  sufficient  to  do  this,  that  of  inflamed  tissues,  which  may  rise  to 
17.5  per  cent.  (Ewald),  is  amply  sufficient.  Even  in  the  blood  of 
asphyxia,  containing  about  12  per  cent.  C02,  appreciable  amounts  of 
salicylic  acid  can  be  set  free  from  its  salts,  and  consequently  it  is  pos- 
sible that  in  inflamed  joints  a  local  antiseptic  action  may  be  exerted 
although  the  salicylate  never  reaches  a  harmful  concentration  in  the 
other  tissues,  especially  the  nervous  system. 

After  absorption  salicylic  acid  is  retained  in  the  blood  in  strikingly 
large  amounts  and  for  a  long  time  (Jacoby  u.  Bondi),  and,  while 
the  bones  contain  very  little,  the  muscles  and  particularly  the  joints 
contain  much  more.  These  findings  also  help  to  explain  the  fact  that 
the  action  of  this  drug  is  to  a  considerable  extent  limited  to  the  joints. 
These  authors  also  found  that  in  the  joints  of  rabbits  infected  with 
staphylococcus  aureus  much  larger  amounts  of  salicylic  acid  were 
present  than  in  those  of  the  controls.  These  results  indicate  that  this 
drug  is  especially  attracted  to  and  retained  by  the  bacteria  localized 
in  the  joints  or  by  the  substances  produced  by  them  in  the  inflamed 
tissue.  Perhaps  under  these  conditions  the  higher  C02  tension  plays  a 
role  in  liberating  salicylic  acid,  which  on  account  of  its  solubility  in 
lipoids  penetrates  into  the  cells  and  remains  in  them. 

THERAPEUTIC  EMPLOYMENT. — In  acute  articular  rheumatism 
sodium  salicylate  is  administered  in  doses  of  3.0-5.0  gr.  per  diem  and 
in  severe  cases  at  the  start  in  doses  of  6.0-10.0  gr.,  which  are  reduced 
later.  While  as  a  result  of  its  administration  not  only  the  fever  but 
also  the  pain  and  swelling  of  the  joints  disappear,  all  too  frequently 
such  doses  cause  disagreeable  side  actions,  resulting  in  the  development 
of  salicylism.  On  account  of  its  irritating  properties,  free  salicylic 
acid  is  no  longer  used  internally.  Inasmuch  as  the  free  acid  is  liberated 
from  the  salicylates  by  the  gastric  HC1,  their  administration  may  also 
cause  symptoms  of  gastric  irritation,  which  are  only  slightly  lessened 
[  ?  TR.]  by  administering  sodium  bicarbonate  with  them.  The  neutral 
esters  of  salicylic  acid  which  are  decomposed  only  when  acted  upon  by 
the  intestinal  ferments,  however,  do  not  irritate  the  gastric  mucosa. 
This  is  the  reason  for  one  important  superiority  of  phenyl  salicylate,  or 
salol,  and  of  acetyl  salicylate,  or  aspirin,  and  of  other  similar  salicylic 
acid  compounds. 

Undesirable  Effects. — In  addition  to  gastric  disturbances,  buzzing 
in  the  ears  is  the  most  common  undesirable  effect  of  the  salicylates. 


ACTION  OF  ARSENICAL  COMPOUNDS  531 

Albuminuria  and  cylindruria  are  also  caused,  even  by  therapeutic 
doses  of  the  salicylate  of  soda,  but  the  evidences  of  renal  irritation 
disappear  after  discontinuance  of  its  administration  (Luthje).  In 
pronounced  salicylism,  vomiting,  excitement,  vertigo,  disturbances  of 
vision,  delirium,  and  even  dyspnoea  (Quincke)  may  occur,  and  very 
large  doses  may  cause  alarming  slowing  of  the  pulse  and  respiration 
with  collapse  and  cardiac  failure. 

In  mild  poisoning  it  is  sufficient  to  discontinue  the  drug,  while  in 
pronounced  poisoning  Ehrmann  states  that  the  administration  of  large 
doses  of  sodium  bicarbonate  may  aid  in  causing  the  more  rapid  elimina- 
tion of  the  salicylates. 

These  disagreeable  systemic  actions  of  the  salicylates  are  due  to 
too  large  amounts  being  absorbed  at  one  time.  After  the  adminis- 
tration of  the  rather  insoluble  esters,  such  as  salol,  the  absorption 
occurs  very  gradually,  for  these  preparations  may  reach  even  the 
lower  portions  of  the  intestines  unaltered, — after  very  large  doses 
salol  appears  in  the  fasces, — salicylic  acid  being  liberated  from  them 
only  gradually.  As  a  consequence,  after  their  administration  salicylic 
acid  is  distributed  throughout  the  body  in  a  constant  but  low  concen- 
tration. For  this  reason  the  curative  effect  of  their  administration 
is  less  striking  and  is  produced  more  slowly. 

Solol  is  usually  administered  in  doses  of  1.0  gm.  five  to  six  times 
a  day.  In  the  same  fashion,  when  acetyl-salicylic  acid  (aspirin), 
acetyl  paramidophenol  (salophen),  or  salicylic  acid,  salicylic  ether, 
(diplosal)  is  administered,  it  is  easier  to  avoid  the  buzzing  in  the  ears 
and  the  other  undesirable  side  actions.  Methyl  salicylates  and  other 
fluid  salicylic  esters  are  applied  locally  to  the  skin,  through  which  their 
absorption  readily  takes  place. 

BIBLIOGRAPHY 

Binz:   Berl.  klin.  Woch.,  1876,  No.  27. 

Binz:  Arch.  f.  exp.  Path.  u.  Pharm.,  1879,  vol.  10,  p.  147. 

Ehrmann:   Munch,  med.  Woch.,  1907,  No.  52. 

Ewald:  Dubois'  Arch.,  1876,  p.  422. 

Jacobi  und  Bondi:  Hofmeister's  Beitr.  z.  physiol.  Chemie,  1906,  vol.  7,  p.  514. 

Liithje:  Deut.  Arch.  f.  klin.  Med.,  1902,  vol.  74. 

Quincke:   Berl.  klin.  Woch.,  1907,  No.  52. 

ACTION  OF  THE  ARSENICAL  COMPOUNDS  ON  PROTOZOA 

The  etiotropic  action  of  quinine  in  malaria  has  shown  that,  in  those 
pathogenic  organisms  which  belong  to  the  class  of  protozoa,  the  sus- 
ceptibility toward  specific  poisons  can  be  greater  than  that  of  the  cells 
of  the  higher  organisms,  and  that  consequently  such  specific  antiseptics 
may  produce  an  internal  disinfection  without  working  injury  to  the 

host. 

ARSENIC  IN  TRYPANOSOME  DISEASES 

Particularly  useful  in  enlarging  our  knowledge  of  the  specific 
etiotropic  relations  of  this  class  of  pathogenic  organisms  has  been  the 


532  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

study  of  the  experimental  chemotherapy  of  the  various  trypanosome 
diseases.  The  causative  agents  of  these  diseases,  to  which  the  African 
sleeping  sickness  and  numerous  animal  and  human  diseases  of  the 
tropics  belong,  may  be  readily  and  successfully  inoculated  into  labora- 
tory animals  such  as  mice,  so  that  trypanosomes  in  large  numbers 
appear  in  their  blood.  In  1902  Laveran  and  Mesnil  found  that  these 
organisms  disappeared  from  the  blood  after  the  subcutaneous  injec- 
tion of  .01  mg.  of  arsenic  trioxide,  and  that  mice,  which  otherwise 
would  have  succumbed  to  the  infection  inside  of  three  or  four  days, 
continued  to  live  for  some  time  longer.  Although  after  a  time  the 
parasites  reappear  in  the  blood,  they  may  again  be  caused  to  disappear 
by  repeating  the  administration  of  arsenic,  but,  unfortunately,  the 
mice  finally,  succumb  to  the  repeated  administration  of  this  drug, 
the  curative  agent  being,  in  comparison  with  its  efficiency  against  the 
pathogenic  organisms,  too  toxic  for  the  host. 

ORGANIC  AESENIC  COMPOUNDS. — The  further  development  of  etio- 
tropic  arsenic  therapy,  which  has,  as  its  last  achievement,  led  to 
Ehrlich's  discovery  of  a  new  cure  for  syphilis,  is  built  up  upon  the 
study  of  the  manner  in  which  complex  metallic  compounds  act  in  the 
body.  As  has  been  previously  explained,  organic*  metallic  com- 
pounds, including  those  of  arsenic,  which  do  not  contain  the  toxic 
element  in  an  ionizable  form,  do  not  exert  the  direct  toxie  actions 
of  their  metallic  constituents.  For  example,  potassium  ferrocyanide, 
whose  solutions  contain  potassium  ions  and  FeCy  ions  but  not  Fe  and 
Cy  ions,  does  not  exert  the  direct  toxic  actions  either  of  iron  or  of  the 
cyanides,  for  in  this  complex  compound  they  are  not  able  to  act  as 
such,  as  they  are  present  in  it  only  in  a  masked  form.  So  long  as  such 
complex  compounds  are  not  broken  up  in  the  body,  they  produce 
only  their  own  peculiar  pharmacological  effects,  but,  when  they  are 
broken  up  so  that  the  metallic  ions  are  liberated,  the  effects  of  these 
latter  are  produced. 

The  ferrocyanide  of  potash  is  consequently  very  slightly  toxic  and, 
as  it  passes  through  the  body  unchanged,  after  its  administration  no 
secondary  effects  from  its  decomposition  products  may  be  observed. 
If,  on  the  other  hand,  such  complex  compounds  are  decomposed  in  the 
body,  the  toxic  action  of  metallic  ions  is  sooner  or  later  exerted,  but, 
as  a  rule,  they  are  exerted  in  different  locations  and  with  different 
intensity  than  when  the  simple  ionizable  compounds  are  administered. 
It  is  just  this  peculiar  property  of  the  complex  organic  metallic  com- 
pounds which  is  decisive  for  their  pharmacological  value. 

The  points  at  which  the  organic  compounds  act  and,  at  the  same 
time,  the  nature  of  their  effects  and  the  order  in  which  they  appear 
depend  on  the  physicochemical  properties  of  the  substances  in  ques- 

*  In  this  section,  by  organic  compounds  are  meant  such  compounds  as 
contain  the  metal  firmly  attached  to  carbon  and  consequently  in  non-ionizable 
form. 


ACTION  OF  ARSENICAL  COMPOUNDS  533 

tion,  these  determining  whether  the  complex  compounds  can  penetrate 
into  various  organs  and  cells  of  the  body,  to  which  the  simple  ionizable 
metallic  compounds  penetrate  either  not  at  all  or  only  in  the  course 
of  very  chronic  poisoning,  in  which  latter  case  they  probably  must 
first  be  changed  within  the  body  into  very  complex  compounds.  Not 
only  the  quantitative  but  also  the  qualitative  differences  observed 
between  acute  and  chronic  metallic  poisoning  are  based  on  such  con- 
siderations. 

•  For  example,  in  acute  lead  poisoning  in  man  the  symptoms  consist 
essentially  of  those  of  gastro-enteritis  and  somewhat  later  of  colic, 
while  only  after  poisoning  lasting  weeks  and  months  do  the  well-known 
lesions  of  the  nervous  and  muscular  systems  develop.  The  same  is 
true  of  experimental  poisoning  with  simple  lead  salts.  If,  however, 
as  in  Harnack's  experiments,  an  organic  complex  lead  compound,  like 
the  triethylate  of  lead,  be  used  to  poison  the  animals,  the  result  is 
very  different,  for,  on  account  of  its  physicochemical  properties,  this 
substance  very  quickly  penetrates  into  nerve  and  muscle  cells  and, 
after  a  rapidly  passing  peculiar  molecular  action,  soon  produces  the 
same  nervous  and  muscular  lesions  as  are  seen  in  chronic  lead  poison- 
ing. It  is  thus  evident  that  this  complex  compound  has  made  it  pos- 
sible for  the  lead  ions,  which  are  contained  in  it  and  which  later  are 
liberated  from  it,  to  be  distributed  about  in  the  body  very  differently 
from  those  ions  which  are  contained  in  the  simple  inorganic  lead  salts. 

In  a  similar  fashion  the  diethylate  of  mercury,  Hg(C2H5)2,  being  a  very 
stable  compound,  causes  at  first  only  very  marked  and  characteristic  toxic  actions 
on  the  central  nervous  system,  while  the  usual  effects  of  mercury  appear  only 
very  much  later  (Hepp). 

The  same  holds  good  for  the  organic  arsenic  compounds,  which,  in 
accordance  with  their  particular  distribution  in  the  organism,  act  on 
the  tissues  in  situations  which  the  ordinary  arsenic  compounds  do  not 
reach  at  all.  It  is  this  which  is  decisive  for  their  value  as  drugs  which 
will  exert  more  or  less  elective  toxic  actions  on  pathogenic  organisms. 

Of  these  organic  arsenic  compounds,  cacodylic  acid  has  been  widely 
used  for  therapeutic  purposes, — for  example,  in  phthisis, — while,  since 
its  recommendation  by  Gautier  in  1896,  it,  as  well  as  other  organic 
arsenic  compounds,  has  been  used  in  the  treatment  of  syphilis.  Caco- 
dylic acid,  however,  is  broken  up  with  too  great  difficulty,  and  conse- 
quently is  not  well  adapted  for  the  production  of  the  etiotropic  actions 
of  arsenic. 

Consequently,  the  stimulus  was  given  for  a  search  for  organic 
arsenical  compounds,  which  were  sufficiently  non-toxic  and  which  could 
be  absorbed  and  carried  about  in  the  organism  in  unaltered  form,  so 
that  they  might  penetrate  into  the  parasites,  in  which  they  might  in 
some  manner  or  other,  probably  in  the  parasites  themselves,  be  trans- 
formed into  products  toxic  for  these  parasites.  The  greatest  value  as 
etiotropic  agents  must  be  possessed  by.  such  organic  compounds  as  are 


534  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

but  slightly  absorbed  or  transformed  by  the  cells  of  the  host,  but  which 
either  penetrate  more  readily  into  the  pathogenic  parasites  or  are  more 
readily  transformed  by  them  into  toxic  substances. 

ATOXYL. — Numerous  experiments  with  etiotropic  arsenic  therapy 
were  first  conducted  with  arsenilic  acid,  or  atoxyl,  which,  was  intro- 
duced into  therapeutics  by  Blumenthal  in  1902.  First  used  in  try- 
panosome  diseases  by  Thomas  in  1905,  the  value  of  this  drug  was 
proven  by  Robert  Koch  in  his  extensive  experiments  in  treating  the 
sleeping  sickness.  While  atoxyl  is  in  large  part  unaltered  in  the  body 
and  circulates  about  in  the  blood  for  a  long  time,  enough  of  it  is 
absorbed  and  transformed  by  the  cells  (Igersheimer  u.  Rothmann)  to 
produce  distinct  effects.  A  certain  proportion,  varying  with  the 
species  of  animal  used,  is  excreted  unchanged  in  the  urine  (Muto), 
while  the  remainder  is  transformed  in  the  body  into  powerfully  toxic 
substances. 

With  the  fixing  of  atoxyl  or  of  its  transformation  products  in  the 
organs  is  combined  the  development  of  specific  pharmacological 
actions,  which  are  not  produced  by  the  inorganic  arsenic  compounds. 
Thus,  in  cats  it  causes  disturbances  of  the  central  nervous  system 
resulting  in  ataxia,  spasms,  and  paresis,  and,  in  dogs,  renal  hemor- 
rhages and  lesions  in  other  internal  organs  (Igersheimer).  In  accord- 
ance with  these  actions,  after  administration  of  atoxyl,  arsenic  is  found 
in  the  cat  chiefly  in  the  central  nervous  system,  but  in  the  dog  chiefly 
in  the  internal  organs  (Igersheimer  u.  Rothmann). 

In  agreement  with  these  experimental  results,  in  man  atoxyl  all 
too  frequently  causes  severe  toxic  effects,  consisting  in  disturbances  of 
the  digestive  system  and  nephritis,  and  in  particular  in  toxic  effects 
on  the  nervous  system  and  on  the  eyes,  as  a  result  of  which  unpre- 
ventable  progressive  impairment  of  vision  and  permanent  blindness 
due  to  optic  atrophy  may  result  from  the  use  of  atoxyl.  For  this 
reason  it  is  of  interest  that  arsenic  may  be  found  in  the  eyes  of 
animals  poisoned  by  atoxyl,  but  not  in  those  of  animals  which  have 
been  poisoned  by  inorganic  arsenic  compounds  and  in  which  optic 
atrophy  has  not  yet  been  observed  (Igersheimer  u.  Rothmann)  *  These 
actions  of  atoxyl  are  probably  to  be  attributed  to  its  transformation 
products.  Similar  effects  result  from  the  administration  of  other  sub- 
stances closely  related  to  it,  such,  for  example,  as  acetyl-arsenilic  acid. 
The  maximum  dose  of  atoxyl  per  dose  and  per  diem  is-  .02  gm. 

Atoxyl  when  continuously  administered  must  also  in  part  be  transformed 
into  some  inorganic  arsenic  compound  or  compounds,  as,  following  its  adminis- 
tration, symptoms  of  conjunctivitis,  rhinitis,  trophic  disturbances  of  the  skin, 
etc.,  occur,  all  symptoms  which  are  characteristic  of  arsenic  poisoning. 

ATOXYL  DERIVATIVES. — Atoxyl  has  been  shown  by  Ehrlich  and 
Bertheim  to  be  sodium  paraminophenyl  arsonate  or  arsanilate.  This 

*  See  page  537. 


ARSENICAL  COMPOUNDS  IN  TRYPANOSOMIASIS     535 

has  served  Ehrlich  as  a  starting-point  for  extensive  experimentation 
with  a  very  large  number  of  related  compounds,  which  he  obtained 
from  atoxyl  by  changing  its  molecule — by  reduction  to  compounds  of 
trivalent  arsenic  and  by  the  introduction  of  different  side  chains.  As 
a  test  object  for  the  curative  value  of  these  compounds  in  protozoal 
infections,  animals  infected  with  trypanosomes  have  been  used. 

The  comparison  of  the  efficiency  of  such  substances  has  disclosed 
certain  relationships  between  their  constitution  and  the  degree  of  their 
etiotropie  actions  (Ehrlich).  Thus,  arsacetin,  obtained  by  the  intro- 
dution  of  an  acetyl  radical  into  the  amido  group  of  atoxyl,  was  found 
by  him  to  be  more  efficient  than  atoxyl.  The  maximal  dose*  of  this 
drug  is  the  same  as  that  of  atoxyl  (0.2  gm.  per  dose  and  per  diem). 

Neither  arsenilic  acid  nor  arsacetin  kills  trypanosomes  in  vitro, 
although  arsenious  acid  and  such  organic  arsenic  compounds  as  contain 
trivalent  arsenic  do  so,  and  it  has  been  established  that  compounds 
containing  pentavalent  arsenic  do  not  produce  a  direct  effect  on 
trypanosomes. 

This  is  in  agreement  with  earlier  experience  with  arsenic  compounds,  for 
arsenic  pentoxide  is  far  less  toxic  to  animal  and  vegetable  organisms  than  arsenic 
trioxide,  so  that  it  has  been  assumed  that  the  pentoxide  as  such  is  non-toxic  and 
becomes  toxic  only  after  it  is  transformed  into  the  trivalent  ion  (Husemann, 
Loew).  The  behavior  of  the  trioxide  and  pentoxide  of  antimony  is  quite 
analogous. 

Atoxyl  and  arsacetin  are  both  compounds  containing  pentavalent 
arsenic,  and  it  is  probable  that  the  curative  action  of  atoxyl  and  of 


/OH 
O  =  As  ^OH  O  =  As  ^-CH3  O  =  As  / 

\OH  \CH3  X)H 

Arsenic  acid  Cacodylic  acid  Phenylarsenic  acid 

NH2  NH'(COCH3) 


X)Na 
>  =  As<( 
X)Na 

Atoxyl,  sodium 
arsanilate 

Am 

\)Na 

Arsacetin 

other  organic  pentavalent  arsenic  compounds  depends  on  their  trans- 
formation into  compounds  in  which  the  arsenic  is  trivalent  and  which 
are  directly  toxic  to  protozoa  (Rohl,  Friedberger) ,  just  as  arsenic 
pentoxide,  according  to  Binz  and  Schultze,  is  in  part  reduced  in  the 
organism  to  arsenous  acid.  In  para-aminophenylarsenous  oxide,  Ehr- 


536  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

lich  has  prepared  from  atoxyl  a  reduction  product  which  is  directly 
toxic  to  trypanosoms  and  immediately  toxic  in  the  same  manner 
as  arsenous  acid,  while  even  large  amounts  of  atoxyl  when  injected 
intravenously  never  produce  toxic  effects  immediately  but  only  after 
a  rather  long  period  of  latency. 

COONa  COONa 
CHa          CH, 

OH       OH 


O  As     =    As  As  =  As 


p-Aminophenyl-  Arsenophenylglycin  Dioxydiamidoarsenobenzol 

arsenoxyd 

Although  from  the  above  facts  it  appears  that  all  compounds  of 
trivalent  arsenic  are  much  more  toxic  for  the  higher  organisms  than 
are  those  of  pentavalent  arsenic,  it  is  possible,  by  introducing  side 
chains  into  organic  compounds  of  trivalent  arsenic,  to  diminish  their 
toxicity  to  such  a  degree  that  they  are  better  borne  by  the  experi- 
mental animals  and  still  remain  directly  toxic  to  the  protozoa.  Thus 
Ehrlich  and  Bohl  were  able  to  cure  even  severe  experimental  trypano- 
somiasis  by  a  single  injection  of  arsenophenylglycin  in  dosage  which 
was  not  dangerous  for  the  host. 

Other  Specific  Trypanosome  Poisons. — Antimonial  compounds,  like 
those  of  arsenic,  have  also  proven  to  be  specific  etiotropic  remedies  in 
trypanosomiasis.  Moreover,  at  a  period  antedating  the  discovery  of 
the  arsenic  therapy  of  these  conditions,  Ehrlich  and  Shiga  discovered 
in  trypan  red,  a  dye  of  the  benzopurpurine  series,  a  drug  which  is 
very  efficient  against  protozoa,  and  since  then  it  has  been  found  that 
parafuchsin  and  tryparosan,  derivatives  of  rosaniline,  even  when 
introduced  into  the  stomach,  can  cure  experimental  trypanosomiasis 
(Bohl,  Marks). 

If  the  trypanosomes  reappear  in  the  blood  of  the  experimental  animals 
after  the  curative  effect  of  the  organic  arsenic  preparations  has  passed  off,  by 
repetition  of  the  injection  they  may  be  caused  to  disappear  again,  but  only  to 
return  once  more.  Such  parasites,  from  animals  which  have  been  repeatedly 
injected,  when  reinoculated  into  other  mice,  show  themselves  resistant  to  this 
remedy  when  it  is  administered  to  these  new  hosts.*  Strains  of  parasites  which 
have  thus  become  resistant  to  arsenilic  acid  also  show  an  increased  resistance  to 
other  arsenic  and  antimony  compounds,  but  not  to  the  specifically  toxic  substances 
of  the  benzopurpurine  and  fuchsin  series  (Ehrlich). 

ARSENIC  IN  SYPHILIS. 

The  Spirochaeta  pallida,  the  pathogenic  organism  of  syphilis,  dis- 
covered by  Schaudinn  and  Hoffmann,  is  also  a  protozoal  organism. 

*  Concerning  similar  augmentation  of  the  resistance  in  infusoria  see  Neu- 
haus,  Arch,  intern,  de  Pharmacodynamie  et  de  Therapie,  1910,  vol.  20,  p.  393. 


ARSENIC  IN  SYPHILIS  537 

The  close  biological  relationship,  which,  according  to  Schaudinn's 
views,  exists  between  trypanosomes  and  spirochjetes,  suggested 
the  employment  of  organic  arsenical  compounds  as  etiotropic  reme- 
dies in  syphilis.*  The  first  clinical  curative  results  were  obtained 
by  the  use  of  large  doses  of  atoxyl  (Salmon,  1907,  Lassar,  and  others). 
Uhlenhut  and  his  collaborators  succeeded  in  experimentally  demon- 
strating the  efficiency  of  atoxyl  in  another  spirochsetal  disease,  the 
spirillosis  of  chickens,  and  soon  after  they  were  able  to  demonstrate  the 
same  for  experimental  syphilis.  However,  it  appears  that,  in  com- 
parison with  its  toxicity  for  the  patient,  the  specific  etiotropic  action 
of  atoxyl  on  the  Spirochasta  pallida  is  too  weak,  for  in  human  syphilis 
only  large  and  dangerously  toxic  doses  are  effective. 

SALVARSAN. — Ehrlich  attributes  the  much  more  powerful  thera- 
peutic action  of  salvarsan,  dioxydiamifloarsenobenzol,  to  the  radical 
containing  the  trivalent  arsenic,  the  importance  of  which  was  rendered 
apparent  in  experiments  with  trypanosomes,  and  also  to  the  introduc- 
tion of  hydroxyl  radicals  in  the  para  position  in  the  molecules,  in 
which  the  amido  radicals  are  in  the  ortho  position  relatively  to  the 
hydroxyl  radicals  (see  formula,  p.  536). 

Hata  was  able  to  produce  pronounced  protective  and  curative  results  in 
numerous  spirilloses  with  this  preparation,  as  also  with  other  arsenophenol 
compounds  containing  hydroxyl  groups  in  the  para  position.  Salvarsan  rapidly 
caused  the  spirillse  of  relapsing  fever  to  disappear  from  the  blood,  and  has  shown 
itself  a  very  powerful  etiotropic  agent  in  the  spirillosis  of  chickens,  in  which 
disease  the  efficient  curative  dose  was  only  1/58  part  of  the  largest  non-lethal 
dose,  while  with  atoxyl  the  curative  dose  was  %  of  the  lethal  dose.  In  rabbits 
it  was  possible,  by  the  subcutaneous  injection  of  1/7  to  1/10  of  the  largest 
non-lethal  dose,  to  cause  the  spirillae  to  disappear  from  the  primary  lesion  in  the 
scrotum  as  early  as  on  the  following  day  (Hata,  Tomasczewski ) . 

With  salvarsan  the  ratio  between  the  etiotropic  efficiency  and  the 
toxicity  is  far  more  favorable  than  in  all  the  other  organic  arsenic 
compounds  thus  far  tested,  and  is  particularly  far  more  favorable  than 
with  atoxyl.  This  has  thus  far  been  confirmed  by  clinical  experience 
in  man,  and  in  particular  salvarsan  does  not  produce  the  same  toxic 
effects  in  the  eye  as  does  atoxyl  (Igersheimer)  .t  In  animal  experi- 
ments also  it  does  not  produce  the  symptoms  characteristic  of  atoxyl 
and  related  compounds  (Igersheimer) . 

This  author  was  able,  after  salvarsan  had  been  injected,  to  recognize  the 
presence  of  arsenic  in  the  syphilitically  infected  cornea  of  rabbits,  but  not  in  other 
portions  of  the  eye  or  in  normal  eyes,  a  finding  which  indicates  that  the  efficient 
arsenical  compounds  combine  with  the  syphilitic  tissues  or  with  the  spirochsete? 
or  their  reaction  products  which  may  be  present  in  such  tissues. 

In  man  the  hydrochloride  of  dioxydiaminoarsenobenzol,  or  salvar- 
san, is  injected  subcutaneously  and  intramuscularly  either  in  alkaline 
solutions  or  in  neutral  suspensions,  and  intravenously  in  alkaline 

*  For  history  of  the  development  of  this  idea,  see  Ehrlich,  Ztschr.  f.  Immuni- 
tatsforsch.,  etc.,  1911,  vol.  3,  p.  1123. 

t  [In  London,  at  the  International  Congress,  Igersheimer  reiterated  this  claim, 
and  a  careful  search  of  the  available  ophthalmological  literature  has  failed  to  show 
any  case  of  such  toxic  action  of  salvarsan  on  the  eye. — TR.] 


538  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

solutions.  The  intravenous  injection  acts  most  quickly  and  intensely 
on  the  symptoms  of  the  early  stages,  but  when  injected  subcutaneously 
it  remains  for  a  very  long  time  at  the  place  of  injection,  and  when 
injected  intramuscularly  is  somewhat  more  rapidly  absorbed.  In  both 
of  these  latter  cases  it  appears  to  form  a  deposit  from  which  it  is  more 
or  less  regularly  and  gradually  absorbed  into  the  body,  but,  owing  to 
the  extreme  irritation  caused  by  its  long-continued  contact  with  the 
tissues,  such  injections  cause  severe  and  persistent  pain,  with  lasting 
infiltration  and  often  extensive  necrosis.  Consequently,  Ehrlich  more 
recently  recommends  that  it  be  administered  in  alkaline  solution  ex- 
clusively by  the  intravenous  route  in  doses  ranging  up  to  0.6-0.8  gm. 

It  would  appear  that  a  general  internal  disinfection  may  be  more 
certainly  obtained  by  a  single  or  several  times  repeated  injection 
of  salvarsan  than  is  attained  when  it  is  injected  subcutaneously  or 
intramuscularly,  in  which  case  it  forms  a  deposit  from  which  it  is 
very  gradually  absorbed.  This  is  in  accord  with  the  experience 
obtained  in  animals,  that  the  parasites  which  have  withstood  the  first 
attack  of  the  remedy  acquire  a  relative  immunity  to  it. 

After  intravenous  injection  salvarsan  is  eliminated  rather  rapidly, 
but  when  injected  subcutaneously,  while  the  elimination  starts  very 
soon,  it  continues  for  about  fourteen  days,  and  after  intramuscular 
injection  somewhat  longer  (Greven).  After  intramuscular  injection 
chickens  remain  immune  to  infection  with  spirillosis  for  30-40  days, 
but  after  intravenous  injection  the  protective  effect  disappears  in 
3^  days  (Hata). 

That  salvarsan  exerts  an  etiotropic  action  on  human  syphilis  is 
indicated  in  the  first  place  by  the  rapid  disappearance  of  the  spirochgetes 
following  its  injection.  In  addition,  this  is  indicated  by  the  fact  that 
the  blood-serum  of  patients  treated  with  salvarsan  appears  to  contain 
specific  antibodies  which  exert  a  curative  effect  in  children  with  heredi- 
tary syphilis  (Scholtz  and  others).  According  to  Ehrlich,  the  forma- 
tion of  these  antibodies  is  due  to  the  destruction  of  the  parasites  by 
this  remedy,  their  decomposition  products  stimulating  the  organism 
to  form  antibodies;  but,  according  to  Friedberger,  salvarsan  itself 
directly  and  markedly  stimulates  the  formation  of  antibodies. 

Salvarsan  has  also  proven  itself  an  efficient  etiotropic  remedy  in 
other  spirochaetal  diseases,  particularly  in  relapsing  fever  (Iversen). 

This  is  not  the  place  to  enter  into  a  discussion  of  the  respective 
fields  and  limitations  of  salvarsan  and  mercury  in  the  treatment  of 
syphilis.  A  combined  alternating  treatment  with  these  two  remedies  * 
would  appear  to  be  theoretically  indicated  by  the  experiences  obtained 
by  "combination  therapy"  in  experimental  trypanosomiasis  and 
spirochaetal  infections  (Tsuzuki).  These  have  shown  that  the  com- 
bination of  several  etiotropic  substances  produces  a  more  energetic 

*  [Practical  experience  has  proven  the  correctness  of  this  theory. — TB.] 


ARSENIC  AND  MERCURY  IN  SYPHILIS  539 

effect  and  a  more  certain  cure  than  would  be  expected  from  the  arith- 
metical sum  of  the  effect  of  the  different  substances  used.  Such  alter- 
nating treatment  with  arsenical  and  mercurial  preparations  would 
appear  to  be  indicated  by  the  fact  that  the  resistance  acquired  by  cer- 
tain protozoa  to  one  group  of  etiotropic  remedies  does  not  extend  to 
remedies  of  a  different  nature,  and  consequently  it  is  probable  that 
those  parasites  which  have  become  resistant  to  one  remedy  and  which 
are  responsible  for  recidivation  may  be  destroyed  by  remedies  of  a 
different  nature. 

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Uhlenhut:  Med.  Klinik,  1911,  No.  5. 

Uhlenhut  u.  Manteufel:  Ztschr.  f.  Immunitatsforschung,  1908,  vol.  1. 

MERCURY  AS  A  SPECIFIC  FOR  SYPHILIS 

Historical. — Mercury  has  long  been  considered  a  specific  against 
the  secondary  symptoms  of  syphilis.  After  having  been  used  even 
earlier  in  the  Orient,  mercurial  preparations  about  the  year  1500 
became  generally  recognized  as  efficient  in  syphilis  when  administered 
internally.  At  this  time  mercury  was  pushed  up  to  the  appearance 
of  severe  toxic  symptoms,  such  as  salivation,  diarrhea,  etc.,  so  that  the 
dangers  which  accompanied  the  treatment  soon  led  to  a  reaction,  as  a 


540  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

result  of  which  physicians  in  the  sixteenth  century  were  divided  into  the 
two  camps  of  mercurialists  and  anti-mercurialists.  Gradually,  how- 
ever, this  opposition,  which  persisted  even  into  the  nineteenth  century, 
has  disappeared  as  physicians  have  learned  how  to  use  the  remedy 
rationally. 

ITS  ETIOTROPIC  ACTION. — That  mercury  exerts  an  action  on  the 
causative  agent  of  syphilis  is  rendered  probable  by  the  fact  that  the 
most  varied  symptoms  of  the  infection  are  equally  influenced  by  it 
and  that  healthy  children  may  be  born  of  syphilitic  parents  who  have 
been  treated  with  mercury,  while,  when  the  parents  have  not  been 
treated  by  mercury,  their  children  are  congenitally  syphilitic.  Thus 
far  it  has  not  been  definitely  proven  that  this  action  on  the  Spiro- 
chaeta  pallida  is  etiotropic  in  the  same  strict  sense  as  is  the  action  of 
quinine  on  malarial  plasmodia,  for  an  indirect  action  on  these  para- 
sites by  stimulating  of  the  formation  of  antibodies  is  conceivable. 
However,  it  is  more  probable  that  this  drug  acts  directly  on  the 
pathogenic  organisms,  for,  in  general,  cures  result  the  more  certainly, 
the  more  completely  and  persistently  the  body  of  the  patient  is  kept 
saturated  with  mercury  to  the  degree  of  tolerance.  It  is  a  recognition 
of  this  fact  which  has  led  to  the  general  adoption  of  the  chronic 
intermittent  mercury  treatment,  in  which  the  infected  individuals  are 
kept  under  the  influence  of  mercury  off  and  on  for  several  years. 

The  excretion  of  mercury  in  the  urine  offers  a  means  of  estimating 
the  amount  of  mercury  circulating  in  the  body  and  the  duration  of  its 
action.  While  after  absorption  mercury  circulates  about  in  the  body 
as  a  compound  of  mercury-albuminate  and  sodium  chloride,  and  is 
chiefly  excreted  in  the  faeces  and  to  only  a  small  extent  in  the  urine, 
still  that  portion  of  the  mercury  which  is  present  in  the  general  circu- 
lation, and  which  passes  through  the  renal  vessels,  probably  maintains 
a  definite  ratio  to  the  amount  excreted  in  the  urine.  The  more  rapidly 
the  mercury  appears  in  the  urine  after  its  administration  in  the  given 
method  the  more  rapidly  and  intensely  are  its  effects  produced,  and 
the  more  rapidly  its  elimination  by  this  channel  diminishes  the  more 
rapidly  does  its  action  in  the  body  pass  off.  Always,  however,  it  con- 
tinues to  be  excreted  for  months,  and,  under  certain  circumstances, 
after  the  urine  has  become  free  from  mercury  it  may  appear  in  it 
again,  both  of  these  facts  proving  that  mercury  is  stored  up  in  differ- 
ent organs,  as  a  result  of  which  poisoning  must  sooner  or  later  result 
if  the  elimination  fails  to  keep  pace  with  the  absorption. 

The  aim  of  every  energetic  antiluetic  mercurial  cure  must  be  to 
maintain  for  a  considerable  time  the  mercury  content  of  the  organism 
at  such  a  height  that,  while  not  causing  toxic  effects,  it  remains  not 
too  far  below  this  toxic  concentration.  A  regular  elimination  of 
mercury  during  the  period  of  administration  and  a  gradual  sinking 
of  the  curve  of  elimination  after  its  cessation  may  serve  as  signs  that 
one  is  close  to  the  attainment  of  such  saturation.  A  temporary  marked 


MERCURY  AS  SPECIFIC  FOR  SYPHILIS  541 

increase  in  the  amount  eliminated,  either  directly  after  its  adminis- 
tration or  in  the  course  of  the  cure,  indicates  a  too  rapid  absorption, 
with  its  accompanying  danger  of  poisoning. 

The  determination  of  the  curve  of  elimination  is,  consequently,  fff 
importance  for  the  determination  of  the  value  of  different  methods  of 
administering  mercury  (Burgi). 

When  mercurial  inunctions  are  given  (of  mercurial  ointment  33 
per  cent.,  daily  3.0-5.0  gm.  for  30-40  days),  mercury  may  be 
recognized  in  the  urine  from  the  first  day  on,  its  elimination  increas- 
ing gradually  up  to  a  certain  point  and  then  remaining  for  weeks 
very  nearly  constant,  and,  after  cessation  of  treatment,  falling  again 
very  gradually.  The  absorption  of  mercury  from  the  ointment  is  due 
in  part  to  the  gradual  change  of  the  metal,  which  has  been  pressed 
into  the  openings  of  the  ducts  of  the  glands  of  the  skin,  into  mercuric 
salts  of  the  fatty  acids,  or  to  its  gradual  change  into  these  same  salts 
by  the  oxygen  of  the  air  acting  under  the  influence  of  the  secretions 
of  the  skin.  As  this  chemical  transformation  occurs  very  gradually, 
local  irritation  does  not,  as  a  rule,  occur.  The  mercury  is  also  to  some 
extent  absorbed  through  the  lungs  as  a  result  of  respiring  such  of  it 
as  is  vaporized  by  the  body  heat. 

BY  INHALATION. — When  present  on  the  surface  of  the  skin,  metallic  mer- 
cury vaporizes  in  sufficient  quantities  to  produce  therapeutic  effects  solely  as  a 
result  of  its  absorption  through  the  lungs.  On  this  fact  is  based  the  employment 
of  mercurial  amalgam,  a  gray  powder  composed  of  aluminum  and  magnesium 
amalgam,  which  is  kept  in  contact  with  the  skin  in  a  small  bag  and  thus  pro- 
vides a  mild  mercurial  treatment.  When  thus  used  its  elimination  follows  essen- 
tially the  same  course  as  in  a  mild  inunction  cure. 

ORAL,  ADMINISTRATION. — When  mercury  is  to^be  administered  by 
mouth,  the  mercurous  compounds  are  usually  employed,  particularly 
calomel,  HgCl  (0.03-0.05  gm.  ter  in  die,  at  times  combined  with 
opium),  and  the  yellow  iodide  of  mercury,  which  is  used  in  the  same 
dosage  as  calomel,  and  which  is  particularly  often  used  in  children, 
in  a  dosage  for  infants  of  0.01  gm.  per  diem.  Although  in  vitro  the 
mereurous  compounds  are  insoluble  in  water,  in  the  body  they  are 
absorbed,  but  when  they  are  administered  internally  the  amount  of 
mercury  eliminated  in  the  urine  shows  very  marked  variations  from 
day  to  day,  due  apparently  to  the  varying  conditions  affecting  absorp- 
tion from  the  intestine.  The  suddenly  increased  absorption  which 
may  occur  when  Hg  is  thus  administered  explains  the  greater  danger 
of  causing  mereurialism  when  mercury  is  administered  internally, 
and  when  it  is  thus  administered  stomatitis  and  diarrhoea  are  observed 
relatively  often. 

For  mercurial  injections  soluble  and  insoluble  preparations  are 
used. 

Of  the  soluble  ones  the  bichloride  is  the  one  most  used,  in  daily 
small  doses  of  0.01  gm.  continued  for  20-40  days.  Its  excretion  in  the 
urine  starts  at  once,  and  if  the  injections  are  given  each  day  the 


542  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

amount  eliminated  rises  gradually  and  regularly  just  as  is  the  case 
in  inunction  cures,  and  when  its  administration  is  stopped  the  amounts 
eliminated  gradually  decrease,  its  elimination  curve  corresponding  to 
that  of  a  gradual  saturation.  Unfortunately,  these  injections  in  many 
cases  cause  pain  and  induration,  even  when  by  addition  of  sodium 
chloride  the  attempt  is  made  to  prevent  the  precipitation  of  mercury 
albuminate  at  the  point  of  injection. 

These  local  effects  cannot  be  certainly  avoided,  even  by  the  use  of  organic- 
compounds  of  mercury  with  formamide,  glycocoll,  etc.,  which  are  soluble  in 
alkaline  media. 

Finely  divided  insoluble  mercurial  preparations,  such  as  calomel, 
thymol-acetate  of  mercury,  salicylate  of  mercury,  etc.,  are  injected 
(suspended  in  liquid  paraffin  or  olive  oil)  in  amounts  of  0.05  to  0.1 
gm.,  at  considerable  intervals, — about  every  six  to  seven  days, — with 
the  idea  of  forming  a  deposit  of  mercury  from  which  absorption  will 
take  place  gradually.  As  a  matter  of  fact,  however,  the  elimination 
curve  after  injection  of  the  widely  used  salicylate  of  mercury  does  not 
indicate  a  gradual  regular  saturation  of  the  organism  with  mercury, 
but,  on  the  contrary,  the  maximal  elimination  occurs  on  the  day  of 
injection  and  sinks  immediately,  rising  with  each  new  injection. 
This  curve  of  elimination  is  in  accordance  with  the  clinical  experience 
that,  although  these  injections  are  very  efficient,  they  are  at  times  dan- 
gerous, for  a  serious  poisoning  may  result  from  the  unexpected  sudden 
absorption  of  large  amounts  of  mercury  from  the  reactively  inflamed 
tissues  around  the  mercurial  deposits. 

After  intravenous  injection  of  the  bichloride,  the  curve  of  elimination 
rises  abruptly  and  falls  again  very  quickly.  When  thus  administered  more  than 
50  per  cent,  is  rapidly  eliminated  from  the  body,  and  for  a  time  so  much  mercury 
is  present  in  the  circulation  that  the  danger  of  causing  toxic  symptoms  is  neces- 
sarily great,  not  to  speak  of  the  danger  of  the  formation  of  thrombi. 

From  the  above  it  is  apparent  that  inunction  cures  best  meet  the 
demand  for  a  gradual  and  even  mercurialization.  [The  translator  is 
among  those  who  are  convinced  that  hypodermic  injections  of  soluble 
mercurial  preparations  have  been  proven  to  be  the  most  rapid  and 
certain  means  of  curing  syphilis  by  mercury.  The  observations  on  the 
disappearance  of  the  Wassermann  under  various  methods  of  treat- 
ment, as  well  as  the  observations  on  its  reappearance  or  failure  to 
reappear,  both  appear  to  indicate  that  this  conclusion,  which  has 
been  based  on  clinical  experience,  is  well  founded. — TR.]  However, 
even  when  mercury  is  thus  administered,  it  is  not  always  possible  to 
avoid  the  symptoms  of  poisoning.  These  start  with  a  metallic  taste 
in  the  mouth,  stomatitis,  and  salivation  (see  p.  513).  Albumi- 
nuria  and  nephritis*  may  also  develop  during  mercurial  cures,  and 
in  severe  poisoning  diarrhoea  occurs.  In  fatal  cases  cardiac  depres- 
sion, sinking  of  the  blood-pressure,  and  collapse  may  result. 

*  [Albuminuria  and  nephritis  are  not  infrequently  manifestations  of  syphilis, 
the  occurrence  of  which  during  the  mercurial  cure  is,  the  translator  believes, 
quite  as  often,  or  more  often,  due  to  the  disease  than  it  is  to  the  remedy. — TB.) 


ANTITOXINS  543 

BIBLIOGRAPHY 
Biirgi:  Arch.  f.  Dermat.  u.  Syphilis,  1906,  vol.  79. 

ANTITOXINS 

Historical. — The  experimental  therapy  of  infectious  diseases  had  its 
origin  in  the  study  of  the  problems  of  immunity.*  In  his  studies  of 
acquired  immunity  Pasteur,  having  observed  that  many  infectious 
diseases  attack  the  same  individual  but  once  and  that  in  such  cases 
a  very  light  attack  appears  to  give  the  same  protection  as  a  severe 
one,  started  a  series  of  logically  planned  laboratory  experiments  in  the 
hope  of  finding  methods  of  treatment  which,  like  light  attacks  of  ill- 
ness, would  give  the  same  immunity  without  injuring  the  animals  ex- 
perimented on.  He  strove  to  reach  the  same  goal  as  had  been  attained 
empirically  by  Jenner  when  he  utilized  the  chance  observation  that  the 
harmless  cowpox  protected  against  the  dangerous  human  smallpox. 

In  1880  Pasteur  succeeded  in  immunizing  animals  against  the  viru- 
lent pathological  organisms  of  chicken-cholera,  and  soon  afterwards  of 
anthrax,  by  inoculating  them  with  artificially  attenuated  bacteria. 
The  discovery  that  the  virulence  of  microbes  may  be  increased  or 
diminished  by  their  passage  through  animals  was  of  great  importance 
in  Pasteur's  later  success  in  discovering  his  method  of  inoculation 
against  rabies.  The  Americans,  Salmon  and  Smith,  while  investigat- 
ing hog-cholera,  1885-86,  were  the  first  to  learn  that  immunization 
could  be  produced  by  injecting  not  only  attenuated  bacteria,  but  also 
their  soluble  metabolic  products,  known  to-day  as  toxins.  Later  on, 
immunization  against  the  bacilli  of  tetanus  and  diphtheria  was  accom- 
plished by  Roux  and  by  Brieger  and  Kitasato,  who  injected  filtrates 
from  bacterial  cultures  for  this  purpose.  While  in  other  cases  it  was 
mt  possible  to  produce  immunity  by  use  of  the  metabolic  products  of 
living  bacteria,  if  the  bacteria  first  be  killed,  it  is  possible  to  produce 
immunity  by  injecting  the  substance  contained  in  the  dead  bodies,  the 
endotoxins.  This  was  first  done  by  Pfeiffer  using  cholera  vibriones. 

Further  progress  in  the  study  of  the  problems  of  immunity  was 
rendered  possible  by  the  discovery  that  the  inoculation  of  animals 
with  gradually  increasing  amounts  of  bacterial  substances  produces 
an  immunization  not  only  against  the  living  pathological  organisms, 
but  also  against  the  injection  of  large  quantities  of  the  same  extremely 
toxic  substances  with  which  they  are  inoculated.  As  a  result  of  the 
recognition  of  this  fact,  it  became  possible  to  investigate  these  problems 
by  quantitative  methods.  

*  In  this  connection  the  authors  will  confine  themselves  to  a  discussion 
of  those  points  bearing  on  immunization  which  are  essential  for  the  understanding 
of  the  now  generally  adopted  method  of  treatment.  More  complete  discussions 
may  be  found  not  only  in  various  monographs  and  larger  works,  but  in  the 
following  works :  Krehl  u.  Levy,  Kap.  Inf ektion  und  Immunitat  in  Krehl's  Pathol. 
Physiologie,  5.  Aufl.,  Leipzig,  1907;  At.  Jakoby,  Immunitat  und  Disposition, 
Wiesbaden,  1906;  Oppenheimer,  Toxine  und  Antitoxine,  Jena,  1904;  Th.  HI  tiller, 
Infektion  und  Immunitat,  Jena,  1904;  Dieudonne,  Immunitat,  Schutzimpfung 
und  Serumtherapie,  6.  Aufl.,  Leipzig.,  1909. 


544  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

Active  and  Passive  Immunity. — Soon  after  Pasteur,  Chauveau,  in 
1881,  showed  that  it  was  possible  to  produce  immunity  by  the  injec- 
tion of  living  pathogenic  organisms  of  full  virulence,  for  the  natural 
protective  powers  of  the  organism  are  able  to  maintain  the  upper  hand 
in  the  strife  against  bacteria,  providing  the  number  of  these  be  small 
or  if  the  conditions  for  their  multiplication  be  unfavorable.  If  the 
organism  overcomes  the  infection  or  the  poisoning  by  toxins,  it  be- 
comes immune  as  a  result  of  the  activity  of  its  own  protective  mechan- 
isms, which  form  antitoxin  and  other  protective  substances.  This  type 
of  immunity,  resulting  from  the  activity  of  the  organism  itself,  is 
known  as  active  immunity,  the  specific  immune  bodies  thus  formed 
circulating  about  in  the  blood,  as  has  been  known  ever  since  Behring  's 
discovery  of  the  antitoxins.  Passive  immunity,  which  results  from  the 
introduction  into  an  animal  of  such  already  formed  immune  sub- 
stances, is  thus  named  because  it  is  produced  without  any  aid  from  the 
individuals  rendered  immune. 

While  in  active  immunity  a  certain  period,  usually  from  five  to 
ten  days  (v.  Dungern),  must  elapse  before  the  development  of  im- 
munity, passive  immunity  is  conferred  immediately  by  the  adminis- 
tration of  the  protective  serum.  Active  immunity  persists  for  a  very 
long  time,  as  those  reactions  of  the  cells  which  result  in  the  formation 
of  the  immune  bodies  persist  for  a  long  time  and  endow  the  organism 
with  the  power  of  making  good  the  loss  of  its  protective  substances. 
Passive  immunity,  on  the  contrary,  persists  for  a  much  shorter  time, 
for  the  substances  which  have  been  derived  from  actively  immunized 
individuals  are  foreign  substances  for  the  passively  immunized  organ- 
ism, and  are  therefore  eliminated  or  combusted  and  are  not  replaced 
by  the  organism. 

In  human  medicine,  except  for  vaccination  against  variola  and 
more  recently  against  typhoid,  active  immunization  is  employed  only 
for  the  treatment  of  rabies. 

BIBLIOGRAPHY 
v.  Dungern:  "Die  Antikorper,"  Jena,  1903. 

VACCINATION  AGAINST  RABIES 

This  disease,  the  pathogenic  organism  of  which  is  not  yet  known, 
is  remarkable  for  its  long  period  of  incubation;  but  Pasteur  discov- 
ered that  the  period  of  incubation  may  be  very  strikingly  shortened 
by  injecting  the  virulent  substances,  obtained  from  the  central 
nervous  system  of  rabid  animals,  directly  into  the  central  nervous 
system  instead  of  into  other  parts  of  the  body.  This  shortening  of 
the  incubation  depends,  as  we  know  to-day,  on  the  fashion  in  which 
the  toxic  substances  are  distributed  throughout  the  body,  for  these 
reach  the  point  at  which  they  act,  the  central  nervous  system,  through 
the  peripheral  nerves,  the  disease  developing  only  when  the  poisonous 
substances  have  reached  these  centres. 


VACCINATION  AGAINST  RABIES  545 

These  findings  of  Babes  and  of  de  Vestea  and  Zagari,  however,  left  it  unset- 
tled whether  it  was  the  pathogenic  organisms  themselves  or  the  poisons  produced 
by  them  which  thus  travelled  along  the  nerves.  Since,  however,  Hans  Meyer  and 
Ransom  have  shown  that  tetanus  and  diphtheria  toxins  are  carried  to  the  central 
nervous  system  by  the  nerves,  it  may  be  assumed  that  direct  inoculation  of  the 
rabies  virus  into  the  central  nervous  system  shortens  the  period  of  incubation, 
because  in  this  case  the  poison  itself  does  not  have  to  pass  along  these  paths. 
The  more  virulent  the  virus  the  more  rapidly  is  the  toxin  manufactured,  and 
consequently  the  shorter  is  the  period  of  incubation,  but  even  with  the  most 
virulent  virus  a  certain  length  of  time  is  needed  for  the  journey  to  the  central 
nervous  system,  varying  with  the  length  of  the  nerve  path  and  amounting  in  the 
rabbit  to  7-8  days  and  in  the  guinea-pig  to  5-6  days. 

By  appropriate  passage  of  the  virus  through  a  series  of  animals 
or  by  heating  it  in  the  absence  of  moisture  for  varying  periods, 
Pasteur  obtained  viruses  of  varying  virulence  and  incubation  period, 
and,  by  inoculating  animals  first  with  the  weak  viruses,  he  was  finally 
able  to  render  them  actively  immune  against  the  most  virulent  viruses. 
In  animals  thus  actively  immunized  the  blood  contains  protective 
substances,  for  when  such  serum  is  inoculated  into  other  animals  it 
protects  them  also  (Babes  et  Lepp}.  Owing  to  the  fact  that  the 
rabies  organism  is  unknown,*  it  cannot  to-day  be  stated  whether  these 
protective  substances  protect  against  the  toxins  produced  by  this 
organism  or  against  the  organism  itself  (Marx}. 

In  any  case  the  efficiency  of  the  Pasteur  prophylactic  treatment  of 
rabies  is  to-day  established  beyond  question.  As  the  treatment  is 
necessarily  always  inaugurated  only  after  infection  has  occurred,  it  is 
evident  that  the  protective  substances  which  are  produced  during 
immunization  must  reach  the  toxins  manufactured  at  the  point  of  in- 
fection before  they  are  carried  to  and  become  combined  with  the 
nervous  centres.  When  the  treatment  is  instituted  promptly  this  is 
possible,  probably  because  the  multiplication  of  the  pathological  organ- 
isms and  the  manufacture  of  the  toxins  at  the  infected  point  go  on 
very  slowly. 

BIBLIOGRAPHY 

Babes  u.  Lepp:  Ann.  de  1'Inst.  Pasteur,  1889,  vol.  3. 

de  Vestea  u.  Zagari:  Ann.  de  1'Inst.  Pasteur,  1889,  vol.  3. 

Harris:  Journ.  of  A.  M.  A.,  1913,  vol.  61,  p.  1511. 

Marx:  in  Kolle-Wassermann's  Hdb.  d.  Infektionskrankheiten,  vol.  4,  p.  1264. 

Moon:  Journ.  of  Inf.  Dis.,  1913,  vol.  13,  p.  232. 

Noguchi:  Journ.  Exp.  Med.,  1913,  vol.  17,  p.  29. 

Poor  and  Steinhardt:  Journ.  Inf.  Dis.,  vol.  12,  p.  202;  vol.  13,  p.  203. 

Williams:  Journ.  of  A.  M.  A.  1913,  vol.  61,  p.  1509. 

Williams:  Journ.  of  Inf.  Dis.,  1913,  vol.  13,  p.  165. 

TUBERCULIN 

Tuberculin  treatment  is  also  based  upon  active  immunization 
(Sahli).  The  various  tuberculins  are  endotoxins  which  may  be  ex- 

*  [Recent  investigations  by  Moon,  NogucM,  Poor  and  Steinhard  and  "Williams 
make   it  probable  that  this   organism   is  no   longer   to  be  numbered  among  the 
unknown   pathological   agents.      Moon   and   Harris   both    report   curative   effects 
from  quinine  in  this  disease. — TE.] 
35 


546  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

tracted  from  the  bodies  of  the  bacteria  only  after  their  death.  The 
various  preparations  used  in  practice  either,  like  old  tuberculin,  con- 
tain those  constituents  of  the  dead  bacteria  which  are  soluble  in 
glycerin  and  water,  or,  like  new  tuberculin,  they  consist  of  a  suspension 
of  very  finely  pulverized  dead  bacterial  bodies.  With  new  tuberculin 
Koch  has  been  able  to  immunize  animals  against  ordinarily  lethal 
infection  with  tubercle  bacilli. 

When  introduced  into  the  body  tuberculin  causes  both  a  systemic 
reaction  and  one  localized  in  tubercular  tissues.  It  is  the  different 
intensity  of  the  reaction  produced  by  tuberculin  in  normal  and  in 
tubercular  animals  and  human  beings  which  is  responsible  for  the 
clinical  significance  of  the  various  diagnostic  tests  (Koch).  While 
tubercular  tissues  exhibit  a  similar  hypersusceptibility  to  certain  other 
substances,  such  as  cantharidin  and  the  albumoses,  still  there  are  quan- 
titative differences  which  make  it  apparent  that  the  reaction  of  tuber- 
culin is  a  specific  one  (see  p.  490).  This  specifically  altered  suscep- 
tibility is  known  as  allergy,  and  in  the  case  of  tubercular  tissues  is 
attributed  by  v.  Pirquet  and  Scliick  to  the  presence  of  a  specific  anti- 
body for  tuberculin  (Moro).  According  to  Wolff-Eisner,  this  anti- 
body sets  free  from  the  tuberculin  certain  substances  which  produce 
an  augmented  endotoxin  action. 


Koch,  R.:  Deut.  med.  Woch.,  1890  and  1897;  1891,  No.  3. 

Moro:   Exp.  u.  klin.  Ueberempfindlichkeit,  Wiesbaden,  1910. 

v.  Pirquet  u.  Schick:   Wien.  klin.  Woch.,  1903,  No.  45. 

Sahli :  Die  Tuberkulinbehdlg.  u.  Tuberkuloseimmunitiit,  Basel,  1910. 

Wolff-Eisner:  Berl.  klin.  Woch.,  1904,  No.  42. 

SERUM  THERAPY 

Serum  therapy  depends  upon  the  fact  that  protective  substances, 
which  have  been  formed  during  active  immunization  in  one  animal, 
may  be  injected  into  a  second  one  (a  human  being) .  Before  discussing 
the  principles  of  serum  therapy  and  the  limits  of  its  efficiency,  it  will 
be  necessary  to  describe  our  present  conceptions  of  the  nature  of  toxins 
and  antitoxins  and  of  their  reciprocal  relationships. 

TOXINS. — The  conception  of  toxins  arose  when  powerful  toxic  sub- 
stances were  found  in  the  pathogenic  micro-organisms  and  their  toxico- 
logical  significance  was  recognized.  At  the  start  there  were  found  in 
the  filtrates  from  bacterial  cultures  soluble  poisons,  which  produced 
the  same  symptoms  as  the  pathogenic  organisms  themselves  (Eoux  et 
Yersin,  Brieger  u.  Frdnkel).  Later  substances  with  similar  toxic 
properties  were  found  in  the  bodies  of  the  bacteria  and  also  in  certain 
poisons  of  animal  origin  and  in  certain  vegetable  seeds.  These  were 
at  first  thought  to  be  true  proteids,  because  they  could  be  precipitated 
from  their  solutions  along  with  the  proteids  also  present  therein. 
However,  we  actually  know  nothing  of  their  true  chemical  nature,  as 


SERUM  THERAPY  547 

no  one  has  thus  far  succeeded  in  preparing  toxins  in  pure  form  and 
consequently  our  conception  of  the  toxins  is  only  a  biological  one. 

These  toxins  are  poisonous  substances  possessing  the  power  of 
stimulating  the  organism  to  form  specific  antidotal  poisons  or  anti- 
toxins. We  know  of  them  that  they  diffuse  with  difficulty  or  not  at  all, 
and  that  consequently  they  are  either  themselves  colloidal  substances 
or,  as  a  result  of  combination  with  proteid  substances,  have  acquired 
colloidal  properties.  Most  of  them  are  very  susceptible  to  heat  and 
light  and  to  exposure  to  air  and  are  chemically  very  labile.  It  is  very 
possible  that  they  actually  are  proteids,  for  their  most  characteristic 
property,  that  of  stimulating  the  organism  to  form  specific  substances 
which  react  with  them,  is  also  a  property  of  non-toxic  proteids  in  so  far 
as  these  reach  the  blood  without  being  denatured.  Moreover,  like  the 
proteids,  the  toxins  are  acted  on  by  enzymes  or  ferments,  a  fact  which, 
taken  with  the  slight  absorption  of  some  of  them,  explains  their  rela- 
tive harmlessness  when  swallowed. 

Toxins  also  show  very  close  analogies  with  the  ferments,  of  whose 
chemical  nature  we  know  quite  as  little.  These,  too,  excite  the  produc- 
tion of  specific  antiferments  in  the  organism,  and  are  characterized, 
like  the  toxins,  by  the  property  of  exerting  their  actions  only  on  cer- 
tain specifically  susceptible  substances.  Like  the  ferments,  the  toxins 
also  are  perhaps  protoplasmoid, — that  is,  they  too  may  possess  certain 
properties  of  living  proteid. 

From  the  above  it  may  be  seen  that  our  knowledge  of  toxins  is 
limited  to  a  knowledge  of  their  toxic  actions  and  of  their  power  of 
stimulating  the  body  to  form  specific  antitoxins.  As  already  men- 
tioned, poisons  of  this  type  are  formed  not  only  by  bacteria,  for  certain 
poisons  of  animal  origin  behave  in  an  entirely  similar  fashion, — for 
example,  the  venom  of  certain  toads,  spiders,  snakes,  scorpions,  and 
bees,  and  many  toxins  derived  from  fishes.  In  addition,  similar  sub- 
stances, known  as  phytotoxins,  occur  in  plants, — for  example,  ricin 
in  ricinus  beans,  crotin  in  croton  seeds,  and  abrin  in  jequirity  beans. 

ANTITOXINS. — The  antitoxins  were  discovered  in  1890  by  Behring 
and  Kitasato,  who  showed  that  animals  could  be  immunized  by  the 
injection  of  the  blood-serum  of  other  animals  which  had  been  actively 
immunized  against  tetanus  and  diphtheria.  Soon  after,  in  1891, 
Ehrlich  showed  the  same  for  ricin  poisoning.  As  the  serum  of  the 
actively  immunized  animal  does  not  contain  even  traces  of  toxin  which 
could  produce  active  immunity  in  the  second  animal,  it  was  evident 
that  during  active  immunization  a  new  substance  must  have  been 
formed  either  out  of  the  original  toxin  or  from  the  body  cells  or 
from  both  together.  This  new  substance  acts  specifically  with  the  toxin 
which  has  been  used  to  produce  active  immunization,  and  with  no 
other. 

Nothing  is  known  of  the  chemical  nature  of  these  antitoxins,  but 
it  is  practically  certain  that  they  are  colloids  of  distinctly  greater 


548 

molecular  weight  than  the  toxins,  for  they  diffuse  much  more  slowly 
than  do  these  (Arrhenius,  Madsen).  Antitoxins,  too,  are  chemically 
labile,  although  in  general  more  stabile  than  the  toxins,  and  many  of 
them  are  not  destroyed  by  heating  up  to  60°  C.,  and  even,  depending 
upon  the  amount  of  salt  present  in  their  solutions,  up  to  nearly  80°  C. 
They  are  also  more  resistant  than  the  toxins  to  the  action  of  acids 
and  alkalies,  and  are  not  so  readily  decomposed  by  exposure  to  light 
and  air. 

From  the  above  it  is  clear  that  the  antitoxins  also  can  be  character- 
ized only  biologically.  They  are  reaction  products  of  the  organism 
which  are  produced  under  the  influence  of  toxins,  and  which  act 
specifically  with  and  render  harmless  only  the  toxin  which  has  stimu- 
lated their  formation.  We  know  nothing  of  their  other  actions  in  the 
body. 

THE  SPECIFICITY  OF  THE  REACTION  BETWEEN  TOXINS  AND  ANTI- 
TOXINS.— In  vitro  the  blood-serum  of  an  animal  immunized  against 
diphtheria  can  render  harmless  only  diphtheria  toxin,  but  not  tetanus 
or  other  toxins,  and  can  protect  other  animals  only  against  lethal  doses 
of  diphtheria  toxin  but  not  against  those  of  other  toxins.  To  explain 
this  it  might  be  assumed,  with  Buchner,  that  both  antitoxins  and  toxins 
react  with  those  body  cells  which  are  susceptible  to  the  toxins,  and  that 
the  antitoxins  when  injected  previously  to  or  simultaneously  with  the 
toxins  are  able  to  interfere  with  the  action  of  the  latter  by  a  physio- 
logical antagonism.  To-day,  however,  we  know  that  Ehrlich's  and 
Behring's  view  is  the  correct  one,  and  that  the  antitoxin  exerts  no 
direct  action  on  the  body  cells  but  reacts  only  with  the  toxin.  In  this 
reaction  the  toxin  is  not  destroyed  by  the  antitoxin,  as  was  at  first 
believed ;  but  the  reaction  between  the  two  substances  consists  rather 
in  a  reciprocal  fixation  or  combination  which  takes  place  in  accord- 
ance with  fixed  quantitative  conditions,  as  has  been  shown  by  Ehrlich 
for  ricin  and  diphtheria  toxins  and  their  antitoxins.  This  reaction 
needs  a  certain  time  for  its  completion  and  proceeds  more  rapidly  at 
high  temperatures  than  at  low.  Whether  the  combination  between 
toxins  and  antitoxins  is  to  be  conceived  of  as  analogous  to  the  combina- 
tion between  weak  bases  and  weak  acids,  or  whether  the  toxin-antitoxin 
reaction  is  reversible  only  with  difficulty  or  not  at  all,  is  still  the  sub- 
ject of  active  discussion  (see  Arrhenius). 

That  the  detoxication  of  toxins  by  antitoxins  is  actually  due  to  the 
formation  of  a  non-toxic  compound  is  proven  by  the  fact  that  in  cer- 
tain cases  it  is  possible  to  separate  the  toxin  and  the  antitoxin  from 
the  compound  which  has  been  formed.  Thus,  Roux  and  Calmette  were 
able,  by  boiling  a  non-toxic  mixture  of  snake  venom  and  antitoxin,  to 
render  it  poisonous  again,  for  this  antitoxin  is  readily  destroyed  by 
boiling  while  the  venom  supports  high  temperatures  much  better. 
Further,  Morgenroth  has  recently  succeeded  in  separating  diphtheria 
toxin  from  its  combination  with  the  antitoxin  by  allowing  acids  to 


SERUM  THERAPY  549 

act  upon  the  compound.  Finally,  in  certain  cases  either  the  free  toxin 
or  free  antitoxin  diffuses  through  certain  membranes,  although  the 
mixture  of  the  two  is  unable  to  do  so  (Martin  and  Cherry). 

FORMATION  OP  ANTITOXINS. — The  manner  in  which  antitoxins  are 
produced  is  entirely  unknown.  Their  specificity  suggested  that  they 
were  formed  from  the  toxins  (Buchner), — that  is,  that  the  organism 
had  the  power  of  changing  the  toxins  into  antitoxins,  which  could 
render  harmless  toxins  subsequently  administered.  If  this  were  so, 
however,  one  would  expect  that  there  would  be  some  quantitative  re- 
lationship between  the  amount  of  toxin  administered  and  of  the  anti- 
bodies formed.  Knorr,  however,  has  shown  that,  after  the  injection  of 
a  certain  amount  of  tetanus  antitoxin,  the  body  produced  enough 
antitoxin  to  neutralize  100,000  times  as  much  toxin  as  had  been 
administered.  Further,  Roux  and  Vaillard,  by  repeatedly  bleeding 
horses  immunized  against  tetanus,  have  been  able  to  remove  from 
them  amounts  of  blood  equal  to  the  total  original  blood  content  of  the 
animals,  without  materially  lessening  the  antitoxic  power  of  the 
blood-serum.  It  is  also  known  that  other  antibodies  related  to  the 
antitoxins,  such  as  the  agglutinins  present  in  the  blood-serum  of  men 
who  have  recovered  from  typhoid,  may  be  demonstrated  in  these 
individuals  for  months  and  years,  although  the  fate  of  the  already 
formed  antibodies  introduced  from  without  shows  that  they  are  grad- 
ually destroyed  or  eliminated  and  disappear  entirely.  It  is,  therefore, 
clear  that  in  actively  immunized  animals  the  antitoxins  must  continue 
to  be  manufactured  for  a  very  long  time.  Thus,  the  quantitative 
disproportion  between  the  toxin  administered  and  the  antitoxin  pro- 
duced and  the  continuation  of  the  formation  of  antitoxin  without 
further  administration  of  toxin  both  render  it  highly  probable  that 
the  antitoxins  are  products  of  the  metabolic  activity  of  the  cells. 

Antitoxins  are,  therefore,  to  be  looked  upon  as  produced  by  specific 
but  still  completely  unexplained  active  processes  in  the  body  cells, 
which  are  excited  by  the  toxins.  Once  these  reactions  have  been 
inaugurated,  they  may  persist  much  longer  than  their  inaugurating 
stimulus,  and,  as  is  the  case  with  other  effects  of  stimuli,  there  is  not 
necessarily  any  fixed  proportion  between  the  amount  of  toxin  adminis- 
tered and  the  products  of  the  reaction  thus  excited. 

Practically  nothing  is  known  as  to  the  place  where  antitoxins  are  formed. 
The  blood  is  looked  upon  simply  as  the  place  where  they  accumulate,  but  not 
as  the  place  where  they  are  formed.  Of  the  various  organs  it  has  been  possible 
only  to  show  that  the  lymphoid  tissues  contain  protective  substances  at  the  com- 
mencement of  active  immunization  before  these  may  be  detected  in  the  serum 
(Pfeiffer  u.  Marx,  Wassermann,  Romer) . 

ANTIGENS  AND  ANTIBODIES. — The  formation  of  antitoxin  is  only  a 
special  instance  of  a  general  reaction  which  follows  the  entrance  into 
the  blood  of  proteid  substances  which  have  not  been  denatured,  for  it 
is  a  general  rule  that,  when  such  substances  penetrate  into  the  blood, 


550  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

the  organism  forms  reaction  products  which  react  specifically  with 
them.  Thus,  after  the  parenteral  introduction  of  heterologous  proteids, 
—whether  these,  like  the  proteids  of  bacteria,  are  toxic,  or  whether, 
like  heterologous  serum,  albumen,  lacto-albumen,  etc.,  they  are  rela- 
tively non-toxic, — precipitins  appear  in  the  blood-serum,  which  react 
specifically  with  the  proteids  in  question  and  form  insoluble  products 
with  them.  When  bacteria  are  injected,  bacteriolysins  are  formed, 
and,  when  normal  cells  are  injected,  specific  cytolysins  or  agglutinins. 
In  these  instances  the  reaction  between  the  antibodies  formed  in  the 
blood  and  the  antigens — that  is,  the  foreign  substances  which  excited 
the  reaction — are  directly  visible.  The  presence  of  other  antibodies, 
as  these  specific  reaction  products  are  generally  named, — for  example, 
that  of  the  antif  erments, — may  be  recognized  in  the  serum  only  by  the 
fact  that  they  inhibit  the  activity  of  the  antigens, — i.e.,  in  the  case 
of  the  ferments  they  inhibit  their  ferment  action.  In  the  same  way 
the  presence  of  antitoxins  is  recognizable  only  from  the  fact  that  the 
serum  prevents  the  toxic  action  of  the  toxins. 

EHRLICH'S  SIDE-CHAIN  THEORY 

While  we  actually  know  nothing  of  the  manner  in  which  antibodies 
are  produced,  according  to  the  views  advanced  by  Ehrlich  and  now 
accepted  by  most  investigators,  the  antibodies  normally  exist  as  ' '  side- 
chains"  in  the  cells  which  produce  them.  According  to  the  hypoth- 
esis, certain  atom  groups  of  the  protoplasm  react  with  the  antigen 
introduced,  and  these  same  atom  groups  under  the  influence  of  the 
reaction  are  manufactured  anew  in  increased  amounts  and  pass  into 
the  blood  as  soluble  reaction  products  which  act  as  antibodies.  So 
long  as  these  reacting  protoplasmic  groups  remain  combined  with  the 
cells,  they  attract  the  antigens  to  the  cells, — i.e.,  they  attract  the 
toxins  to  the  point  at  which  they  exert  their  toxic  action.  When,  how- 
ever, they  are  present  in  the  blood  as  antitoxins,  by  their  affinity  to 
the  toxins  they  divert  them  from  their  point  of  reaction,  the  specifically 
susceptible  elements  in  the  cells. 

Toxoids. — A  matter  of  great  importance  in  the  further  development  of  the 
theories  of  immunity  was  the  behavior  of  certain  substances  which  are  readily 
formed  from  the  toxins,  and  which,  while  relatively  non-toxic,  are  still  able  to 
combine  with  antitoxin. 

Ehrlich,  during  his  investigations  of  diphtheria  toxins,  was  the  first  to  find 
such  substances,  named  by  him  toxoids.  This  author  found  that  there  was  a 
parallelism  between  the  toxic  action  and  the  power  of  combination  with  antitoxin 
only  in  freshly  prepared  solutions  of  diphtheria  toxins,  and  that,  when  the  solu- 
tions were  allowed  to  stand  for  a  time,  their  toxicity  decreased,  but  their  power 
to  neutralize  antitoxin  persisted,  as  did  that  of  stimulating  the  formation  of 
antitoxin.  To  explain  these  facts  Ehrlich  assumes  two  types  of  atom  groups  in 
the  toxin  molecule, — a  combining  or  haptophoric  group,  by  which  the  toxin  is 
anchored  to  the  cell  protoplasm  and  by  means  of  which  it  combines  with  antitoxin, 
and  a  toxophoric  group,  the  loss  of  which  robs  the  toxin  molecule  of  its  typical 
toxic  actions.  These  toxophoric  groups  are  lacking  in  the  toxoids,  which,  how- 
ever, through  their  haptophoric  groups  are  still  able  to  attach  themselves  to  the 


EHRLICH'S  SIDE-CHAIN  THEORY  551 

protoplasm  of  the  cells,  thus  stimulating  the  production  of  antibodies,  and  to 
react  with  the  antitoxin  in  the  same  way  as  the  entire  original  toxic  toxin 
molecule. 

This  parallelism,  between  the  capacity  of  combining  with  antitoxin  in  vitro 
and  that  of  exciting  the  formation  of  antitoxin,  led  Ehrlich  to  assume  that  the 
same  atom  groups  are  responsible  for  the  combination  of  antigen  with  antitoxin 
and  for  its  reaction  with  the  cells  of  the  organism,  and,  according  to  his  theory, 
this  stabile  combination  between  toxin  and  cell  protoplasm  is  the  cause  of  the 
production  of  antibodies,  while  the  typical  toxic  action  of  toxin  has  nothing 
to  do  with  it.  The  fact  that  the  production  of  antibodies  may  be  excited  by 
toxoids  as  well  as  by  toxins  is  thus  explained,  as  is  also  the  fact  that  the 
toxins  excite  their  production  only  in  case  the  cells  are  not  too  severely  damaged 
by  their  toxic  action.  In  accordance  with  this  assumption,  those  cells  which 
have  not  been  at  all  damaged  by  the  specific  toxic  action  of  the  toxin  can  also 
take  part  in  the  production  of  antitoxin,  if  the  toxin  simply  combines  with  their 
protoplasm. 

It  is  thus  apparent  that,  according  to  Ehrlich's  side-chain  theory, 
the  antibodies  are  those  atom  groups  of  the  protoplasm  which  react 
in  the  cells  with  the  antigens  and  are  then  formed  in  excessive  amounts 
and  cast  off  into  the  blood.  This  theory,  however,  does  not  tell  us  why 
the  superfluous  new  formation  and  casting  off  of  side  chains  occurs 
during  the  manufacture  of  antibodies.  Ehrlich  himself  draws  an 
analogy  between  the  phenomena  resulting  from  damage  to  the  proto- 
plasm by  foreign  substances  and  the  morphological  phenomena 
observed  following  trauma  of  the  tissues,  in  which  not  only  the  cells 
which  have  perished  are  replaced  but  in  which  there  always  occurs 
a  distinct  over-production. 

BIBLIOGRAPHY 

Arrhenius:   Immunochemie  in  Ergebn.  d.  Physiologie,  1908,  vol.  7,  p.  480. 
Aschoff:  Die  Seitenkettentheorie,  Jena,  1902. 
Behring  u.  Kitasato:  Deut.  med.  Woch.,  1890. 
Behring  u.  Kitasato:   Ztschr.  f.  Hyg.,  1890. 
Brieger  u.  Frankel:   Berl.  klin.  Woch.,   1890. 
Buchner:   Munch,  med.  Woch.,  1893,  p.  449. 
Ehrlich:  Deut.  med.  Woch.,  1891. 
Ehrlich:  Klin.  Jahrbuch,  1897,  vol.  6,  p.  299. 
Ehrlich:  Deut.  med.  Woch.,  1898,  vol.  24,  p.  38. 
Knorr:  Fortschr.  der  Medizin,  1897,  vol.  15. 
Knorr:   Habilitationsschrift,  Marburg,  1895. 
Martin  and  Cherry:   Proc.  Roy.  Soc.,  1898. 
Martin  and  Cherry:  Brit.  Med.  Journal,  1898. 
Morgenroth:  Virchow's  Arch.,  1907,  vol.  190. 
Pfeiffer  u.  Marx:   Ztschr.  f.  Hyg.,  1898,  vol.  27,  p.  272. 
Romer:  Arch.  f.  Ophthal.,  1901,  vol.  52,  p.  72. 
Roux  et  Calmette:  Ann.  de  1'Inst.  Pasteur,  1895,  p.  225. 
Roux  et  Vaillard:  Ann.  de  1'Inst.  Pasteur,  1893. 
Roux  et  Yersin:  Ann.  de  1'Inst.  Pasteur,  1888,  vol.  2;   1889,  vol.  3. 
Wassermann:  Berl.  klin.  Woch.,  1898,  p.  209. 

ANTITOXIC  SERA 

Antitoxic  sera  are  employed  in  the  treatment  of  diphtheria, 
tetanus,  dysentery,  and  snake  bites.  Practically  the  most  important 
point  in  connection  with  their  preparation  is  the  securing  of  the  high- 
est possible  percentage  of  antitoxin  in  the  serum  of  the  immunized 
animals.  By  quantitative  experiments,  Ehrlich  has  been  able  to 
show  that  the  higher  an  animal  is  immunized  the  larger  the  amount 


552  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

of  antitoxin  accumulated  in  its  blood.  After  a  latent  stage  of  about 
5  days  the  antitoxin  content  of  the  serum  progressively  increases  until 
the  maximum  is  reached,  with  diphtheria  at  the  end  of  10  days  and 
with  tetanus  at  the  end  of  17  days,  after  which  the  antitoxin  content 
sinks,  to  rise  again  after  some  weeks  and  then  to  remain  constant  for 
a  long  time. 

When  the  immune  serum  is  injected  subcutaneously  into  a  second 
organism,  the  antitoxin  is  slowly  absorbed  and  remains  in  the  blood 
for  a  considerable  period.  Thus,  Knorr  found  that  tetanus  antitoxin 
attained  its  highest  concentration  in  the  blood  only  at  the  end  of 
24-48  hours  after  the  injection,  and  that  the  concentration  then  sank 
gradually  so  that  it  disappeared  from  the  blood  at  the  end  of  three 
weeks. 

It  is  thus  seen  that,  while  passive  immunity  never  lasts  so  long  as 
active  immunity,  a  single  injection  of  diphtheria  or  tetanus  serum  still 
confers  a  protection  lasting  for  several  weeks.  This  relatively  long 
stay  of  the  antitoxins  in  the  blood  renders  it  probable  either  that  they 
are  chemically  closely  related  to  the  normal  blood  proteids  or  that  they 
circulate  about  in  the  blood  in  combination  with  proteids  (Homer}. 
Ehrlich  has  shown  that  milk  contains  antitoxin,  and  that  consequently 
protective  substances  may  be  transferred  from  the  nursing  mother 
to  the  infant. 

LIMITS  OP  THEIR  CURATIVE  POWERS. — "While  the  antitoxins  are  pres- 
ent in  all  the  body  tissues,  although  in  slighter  quantities  than  in  the 
serum,  they  probably  do  not  penetrate  into  the  interior  of  the  cells. 
This  is  the  case,  at  least,  with  a  number  of  the  most  thoroughly  studied 
antitoxins, — for  example,  the  tetanus  antitoxin  and  probably  also  the 
diphtheria  antitoxin.  This  inability  of  the  toxins  to  follow  the  anti- 
toxins into  the  cells  determines  the  limit  of  the  curative  action  of 
a  serum  when  once  the  illness  has  developed.  Probably  the  antitoxins 
are  not  able  to  exert  any  curative  effects  on  damage  which  has  already 
been  suffered  by  the  cells  which  are  susceptible  to  the  toxins,  but  are 
able  only  to  prevent  their  further  permeation  with  toxins  and  thus  to 
prevent  any  further  damage  to  the  tissues.  In  the  sections  on  the 
serum  treatment  of  tetanus  and  diphtheria,  the  effects  of  the  serum 
treatment  of  such  conditions  will  be  further  discussed. 

BIBLIOGRAPHY 

Ehrlich:  Deut.  med.  Woch.,  1891,  No.  32. 
Ehrlich:   Ztschr.  f.  Hyg.,  1892,  vol.  12,  183. 
Knorr:  Habilitationsschrift,  Marburg,  1895. 
Romer:   Beitr.  z.  exp.  Therapie,  1905,  No.  9. 

TETANUS 

In  this  disease  the  characteristic  symptoms  are  not  caused  by  a 
general  invasion  by  the  pathogenic  agents,  but  result  from  the  absorp- 
tion and  distribution  of  the  soluble  toxins  which  are  formed  at  the  site 


TETANUS  553 

of  the  infection.  Consequently,  in  animal  experiments  the  symptoms 
which  follow  the  administration  of  tetanus  toxin  are  entirely  similar 
to  those  resulting  from  infection  with  the  tetanus  bacilli.  In  man,  as 
certain  muscle  groups  are  predilectively  affected,  the  order  in  which 
the  symptoms  develop  is  not  so  regular  as  in  animal  experiments,  in 
which  three  stages  may  be  differentiated: 

1.  Localized  tetanus,  a  tonic  stiffness  of  the  muscles,  which  in  most 
species  of  animals  commences  in  the  muscles  in  the  neighborhood  of 
the  point  of  infection  or  injection. 

2.  A  stage  in  which  the  muscles  in  the  neighborhood  of  those  first 
affected  are  successively  involved. 

3.  A  stage  with  general  reflexly  excitable  convulsions,  essentially 
resembling  the  convulsions  caused  by  strychnine. 

In  animals  the  first  symptoms  occur  after  an  incubation  period 
ranging  from  8  hours  up  to  a  number  of  days. 

The  effects  of  tetanus  toxin  differ  from  those  of  strychnine  chiefly 
in  the  long  period  of  incubation  and  in  the  occurrence  of  tonic  muscu- 
lar rigidity,  and  particularly  in  the  occurrence  of  a  localized  tetanus. 

The  manner  in  which  tetanus  develops  at  first  suggested  that  it 
was  due  to  a  pathologically  augmented  excitability  of  some  elements  in 
the  periphery,  but  the  incorrectness  of  this  view  is  shown  by  the  fact 
that  curarization  or  section  of  the  nerves  for  a  time  absolutely  prevents 
the  local  contractures.  These  have  been  explained  by  the  peculiar 
fashion  in  which  this  toxin  is  distributed  throughout  the  body,  H. 
Meyer  and  Ransom  having  shown  that  this  toxin  possesses  a  peculiar 
affinity  for  nervous  substances,  and  is  transported  to  the  central 
nervous  system  exclusively  through  the  peripheral  nerve-endings  and 
not  at  all  through  the  blood.  This  transportation  via  the  nerves  ex- 
plains the  fact  that  in  animals  the  localized  tetanus  spreads  from  the 
muscles  innervated  by  one  spinal  segment  to  those  innervated  by  the 
neighboring  segments. 

When  introduced  into  the  stomach,  tetanus  toxin  produces  no  poisonous 
effects,  partly  because  it  is  absorbed  with  difficulty  but  chiefly  because  it  is 
rapidly  rendered  innocuous  by  the  digestive  juices,  especially  by  the  combined 
action  of  bile  and  pancreatic  juice  (Ransom,  Carriere,  Nencki).  After  intra- 
venous injection  it  disappears  from  the  blood  in  a  few  minutes  (Decroly),  and 
after  subcutaneous  injection  it  is  so  quickly  absorbed  that  rats  in  which  it  has 
been  injected  into  the  tail  can  no  longer  be  saved  by  amputating  the  tail  at  the 
end  of  two  or  three  hours,  showing  that  the  toxin  must  therefore  be  rapidly 
removed  from  the  point  of  infection  although  the  symptoms  do  not  appear  for  a 
long  time.  By  biological  methods,  toxin  may  be  demonstrated  in  the  peripheral 
nerves  at  the  point  of  injection,  it  being  present  in  considerable  amounts  in  the 
sciatic  nerve  1%  hours  after  injection  into  the  leg,  although  at  this  time  none 
can  be  demonstrated  in  the  blood,  muscles,  or  fat  (H.  Meyer  u.  Ransom,  Marie). 
As  this  elective  absorption  by  the  nerve-trunks  occurs  only  when  the  axis-cylinder 
is  intact,  being  greatly  delayed  by  section  and  entirely  prevented  by  degeneration, 
it  is  probable  that  the  nerve-fibrils  themselves  and  not  the  lymphatics  of  the 
nerves  are  the  path  by  which  the  toxin  reaches  the  central  nervous  system. 

From  the  above  it  appears  that,  as  a  result  of  its  great  affinity  for 
nervous  tissues,  tetanus  toxin  is  first  absorbed  by  the  intramuscular 


554  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

nerve-endings  at  the  point  of  injection  or  at  the  point  where  it  is 
manufactured.  It  is  then  transported  by  these  peripheral  nerves  to 
the  corresponding  segment  of  the  cord,  from  which  it  then  spreads  to 
the  neighboring  segments,  at  first  to  those  on  the  injected  side. 
Progressively  other  portions  of  the  spinal  cord  become  affected  until, 
in  the  final  stage,  general  muscular  rigidity  and  increased  reflex 
excitability  develop. 

Although  a  portion  of  the  tetanus  toxin  always  passes  into  the 
lymph  and  the  blood,  it  cannot  pass  from  these  fluids,  directly  into  the 
spinal  cord,  but  must  be  absorbed  by  the  terminal  organs  of  other 
motor  nerves,  through  which  it  then  may  travel  to  the  nervous  centres. 

Under  experimental  conditions,  and  also  often  under  clinical 
conditions,  the  absorption  in  the  peripheral  nerves  in  the  region  of  the 
injection  or  production  of  the  toxin  preponderates,  and  consequently 
cutting  the  nerve — for  example,  when  the  toxin  is  injected  into 
a  leg  section  of  the  sciatic — will  protect  the  animal  from  ordinarily 
lethal  doses.  Hans  Meyer  was  able  definitely  to  prove  that  this 
toxin  travelled  to  the  centres  in  the  nerves,  by  experiments  in 
which  he  was  able  to  block  the  path  for  the  absorption  of  the  toxin 
by  previously  injecting  antitoxin  into  the  nerves.  Under  these  con- 
ditions it  is  detoxicated  by  the  antitoxin  as  it  travels  along  the  nerves, 
so  that  ordinarily  lethal  doses  produce  no  effects. 

It  is  this  absorption  of  the  tetanus  toxin  by  the  nervous  tissues 
which  determines  the  limits  of  the  curative  powers  of  the  antitoxin. 
As  the  central  nervous  system  and  the  peripheral  nerves  do  not  absorb 
the  antitoxin  from  the  blood,  even  a  very  large  amount  of  antitoxin  in 
the  blood  will  not  prevent  animals  from  fatal  poisoning,  if  the  toxin 
be  injected  directly  into  a  nerve-trunk,  for  the  antitoxin  can  reach 
and  detoxicate  only  that  portion  of  the  tetanus  which  has  not  yet  been 
absorbed  at  the  point  of  injection  or  production  and  such  of  it  which 
although  absorbed  into  the  blood  has  not  yet  been  absorbed  by  the 
nerve-endings.  This  is  the  reason  why,  although  the  prophylactic 
effect  of  subcutaneously  or  intravenously  injected  antitoxin  is  certain, 
its  curative  effect  is  very  slight.  It  can  cure  only  in  case  a  lethal  dose 
has  not  already  been  absorbed  by  the  nerves  before  the  antitoxin  is 
injected,  and  consequently  its  effects  are  determined  by  the  period 
which  has  elapsed  between  the  administration  of  the  toxin  and  that  of 
the  antitoxin.  The  same  amount  of  antitoxin  which,  when  injected 
with  a  many  times  lethal  dose  of  toxin,  certainly  protects  the  experi- 
mental animals,  fails  to  do  this  if  it  be  administered  a  few  moments 
later  than  the  toxin,  40  times  the  amount  of  antitoxin  being  necessary 
at  the  end  of  one  hour,  while  after  the  lapse  of  5  hours  a  dose  600  times 
as  large  is  ineffectual  (Do'nitz).  If  a  dangerously  large  amount  of 
toxin  has  already  been  absorbed  into  the  peripheral  nerves,  the  pre- 
vention of  the  invasion  of  the  centres  by  the  toxin  may  be  hoped  for 
only  if  the  antitoxin  be  directly  injected  into  the  nerves  in  the  neigh- 


TETANUS  555 

borhood  of  the  injection  or  site  of  infection.  While  cures  have  been 
obtained  in  a  number  of  desperate  cases  by  using  the  antitoxin  in  this 
fashion,  once  the  centres  have  been  attacked  by  the  toxin,  subcutaneous 
or  intravenous  injection  of  even  very  large  amounts  of  antitoxin  is 
almost  invariably  ineffectual. 

In  accordance  with  these  experimental  results,  clinical  experience 
has  also  shown  that,  when  once  the  symptoms  of  tetanus  have  appeared, 
it  is  no  longer  possible  to  secure  a  cure  even  by  enormous  doses  of  anti- 
toxin. On  the  other  hand,  the  certain  prophylactic  effect  of  tetanus 
serum  is  explained  by  the  mass  action  of  the  antitoxin  in  the  blood 
and  fluids  of  the  body,  as  a  result  of  which  the  toxin  is  kept  from  com- 
bining with  the  nervous  tissues. 

The  long  period  of  incubation  for  tetanus  has  been  explained  by  the  recog- 
nition of  the  manner  in  which  the  toxin  reaches  the  central  nervous  system 
through  the  peripheral  nerve,  and  its  length  has  been  shown  to  depend  almost 
entirely  on  the  length  of  the  nerve  path  which  must  be  traversed  before  reaching 
the  centres.  Consequently,  in  larger  animals  the  incubation  period  is  much  longer 
than  in  smaller  ones.  However,  even  when  the  toxin  is  introduced  directly  into 
the  spinal  cord,  some  time  must  elapse  before  symptoms  appear.  This  time  is 
evidently  necessary  for  the  completion  of  the  reaction  between  the  poison  and 
the  susceptible  elements  of  the  cord,  for,  like  other  ferment  reactions,  many  toxic 
reactions  also  proceed  but  slowly.  A  certain  temperature  has  also  been  shown 
to  be  necessary  for  this  reaction.  Thus,  bats  when  kept  sleeping  at  low  tempera- 
tures manifest  a  very  high  resistance  to  tetanus  toxin  ( Meyer  u.  Halsey ) ,  and  in 
cold-blooded  animals  tetanus  toxin  under  ordinary  conditions  remains  ineffective. 
However,  as  shown  by  Courmont  and  Doyon,  tetanus  develops  even  in  frogs  after 
a  certain  latent  period  if  they  be  kept  in  water  at  a  temperature  of  32°  C. 
Morgcnroth's  experiments,  in  which  frogs  did  not  develop  tetanus  when  kept 
at  low  temperatures  but  quickly  did  so  after  they  had  been  brought  into  warmer 
water  even  a  long  time  after  the  toxin  had  been  injected,  show  that  the  toxin 
reaches  the  central  nervous  system  at  ordinary  temperatures  and  that  the  high 
temperature  is  necessary  only  that  the  toxin  may  become  active  in  the  centres. 

BIBLIOGRAPHY 

Carriere:  Ann.  de  1'Inst.  Pasteur,  1899,  vol.  13,  p.  435. 

Courmont  et  Doyon:   Le  Tetanus,  Paris,  1895. 

Decroly  et  Ronsse:   Arch,  de  Pharmacodyn.,  1899,  vol.  6,  p.  211. 

Donitz:   Deut.  med.  Woch.,  1897,  p.  428. 

Marie  et  Morax:  Annales  de  1'Institut  Pasteur,  1902,  vol.  16,  p.  918;   1903,  vol. 

17,  p.  335. 

Meyer  u.  Halsey:  Jaffes  Festschrift,  Brunswick,  1901. 
Meyer,  H.,  u.  Ranson:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  49. 
Morgenroth:   Arch,  intern,  de  Pharmacodyn.,  1900,  vol.  7. 
Nencki,  Sieber  u.  Scumow-Simanowski :   Zbl.  f.  Bakt.,  1898,  vol.  23,  p.  480. 
Ransom:  Deut.  med.  Woch.,  1898,  p.  117. 

DIPHTHERIA 

In  general  similar  conditions  influence  the  actions  of  the  antitoxin 
in  this  disease,  but  the  manifold  actions  of  the  diphtheria  toxin  furnish 
more  favorable  opportunities  for  this  drug  to  act  than  is  the  case  with 
tetanus. 

This  toxin  also  is  ineffective  when  introduced  into  the  stomach. 
When  absorbed  into  the  blood,  its  effects  correspond  in  general  to 
the  general  effects  produced  by  the  bacteria,  though  in  this  disease  we 


556 

are  probably  not  dealing  with  a  single  poison  but  with  a  mixture  of 
several  different  ones.  They  affect  primarily  the  tissues  with  which 
they  first  come  in  contact,  and  consequently  clinically  they,  as  a  rule, 
first  cause  a  diphtheritic  inflammation  of  the  mucous  membranes,  with 
the  formation  of  a  membrane.  When  distributed  throughout  the 
body,  these  toxins  act  on  many  different  tissues,  as  is  evidenced  by  the 
toxic  decomposition  of  the  proteids,  the  alteration  of  metabolism,  and 
the  character  of  the  post-mortem  findings  in  different  organs,  particu- 
larly the  hemorrhages  and  hyperagmia  of  the  suprarenals.  The  lethal 
effects  are  due  chiefly  to  a  typical  depression  of  all  the  nervous  centres. 
In  experiments  on  animals,  there  are  also  late  developing  paralyses  of 
the  nerves  in  the  neighborhood  of  the  point  of  infection,  which  in  their 
nature  correspond  to  the  postdiphtheritic  paralyses  observed  in  man. 

This  toxin  disappears  very  rapidly  from  the  blood,  for,  when  it  has  been 
injected  intravenously,  blood  infused  into  a  second  animal  exhibits  toxic  proper- 
ties only  if  transfused  within  the  first  4-7  minutes.  In  spite  of  this,  however, 
symptoms  of  poisoning  become  manifest  only  after  many  hours,  even  after  the 
administration  of  many  times  lethal  doses.  In  such  case  the  experimental 
animals  lose  their  power  of  maintaining  their  normal  positions  and  become 
paralyzed,  while,  after  a  temporary  rise,  the  temperature  falls  progressively, 
the  reHexes  disappear,  and  all  functions  of  the  central  nervous  system  fail, 
death  occurring  as  a  result  of  paralysis  of  the  respiration. 

During  the  development  of  the  poisoning  the  blood-pressure  sinks  in  a  stair- 
like  fashion,  and  the  heart,  which  at  the  beginning  of  this  fall  was  still  beating 
powerfully,  beats  more  and  more  weakly,  so  that  after  a  time  cardiac  death 
occurs,  even  if  artificial  respiration  be  carried  on.  It  has  been  shown  that  these 
effects  on  the  circulation  are  at  the  start  chiefly  due  to  central  vasomotor  depres- 
sion, but  that  in  the  final  stages  this  is  accompanied  by  a  direct  toxic  action  on 
the  cardiac  muscle. 

It  has  been  shown  by  Meyer  and  Ransom  that  this  toxin  also  may 
reach  the  centres  via  the  peripheral  nerves,  for,  when  injected  directly 
into  the  nerve-trunks,  it  causes  a  paralysis  of  the  corresponding  cen- 
tres more  rapidly  and  in  smaller  doses  than  when  injected  subcu- 
taneously.  Moreover,  even  if  the  wound  at  the  point  of  injection  into 
the  nerves  be  bathed  with  antitoxin,  or  if  large  quantities  of  antitoxin 
be  administered  intravenously  prior  to  the  intraneural  injection  of  the 
toxin,  the  local  paralysis  still  develops.  It  consequently  is  apparent 
that  it  is  quite  as  difficult  for  the  diphtheria  antitoxin  as  it  is  for  the 
tetanus  antitoxin  to  combine  with  the  toxins,  once  they  have  been 
absorbed  into  the  nerves.  In  any  case,  even  if  the  antitoxin  is  able 
to  penetrate  into  the  central  nervous  system,  it  can  render  harmless 
such  toxin  as  has  already  combined  with  nervous  tissues  only  if  it 
follows  it  there  very  quickly.  Two  hours  after  the  injection  of  toxin 
ten  times  as  large  doses  of  antitoxin  are  necessary  to  secure  the  cura- 
tive effects  as  are  necessary  within  the  first  hour  (Bergkaus,  Marx). 

From  the  above  it  would  appear  that  the  effect  of  the  diphtheria 
serum  is  due  only  to  its  power  of  protecting  against  the  further  absorp- 
tion of  new  toxin  from  the  points  at  which  it  is  produced,  and  not  to 
its  possessing  any  true  curative  action.  This  is  in  accordance  with  the 


DIPHTHERIA  ANTITOXIN  557 

clinical  experience  that,  if  severe  general  symptoms  of  depression  of 
the  centres,  such  as  are  seen  in  very  virulent  infections,  have  already 
developed,  these  cannot  always  be  caused  to  disappear  by  the  adminis- 
tration of  serum.  The  often  astonishing  changes  in  the  symptoms 
which,  in  less  severe  infections,  usually  follow  the  administration 
of  antitoxin,  particularly  when  the  serum  is  used  early,  may  be  ex- 
plained on  the  assumption  that  new  toxin  can  no  longer  reach  the  cen- 
tral nervous  system,  and  that  the  effects  of  that  which  has  already 
been  combined  there  can  still  be  overcome  by  the  cells  affected. 

However,  more  recent  experiments  (F.  Meyer)  show  that  it  is  still  pos- 
sible to  secure  a  cure  by  the  intravenous  injection  of  very  large  doses  of  serum 
even  6-8  hours  after  the  injection  of  the  toxin,  and  consequently  it  is  not  im- 
possible that  the  antitoxin  by  a  mass  action  may  attract  to  itself  toxin  which 
has  already  combined  with  the  nervous  centres.  On  the  other  hand,  this  is  con- 
tradicted by  the  experience  of  most  observers  that  the  postdiphtheritic  paralyses 
are  not  influenced  by  the  serum  treatment.  Recently,  however,  favorable  results 
have  been  claimed  from  the  use  of  very  large  doses  of  serum  in  cases  of  post- 
diphtheritic  paralysis  (Comby). 

It  would  therefore  appear  to  be  certainly  proven  only  that  the 
antitoxin  protects  the  nervous  system  and  other  cells  against  further 
absorption  of  the  toxins.  Consequently  the  earliest  possible  adminis- 
tration of  the  antitoxin  serum  is  of  the  utmost  importance.  Intra- 
venous administration  permits  the  antitoxin  to  become  effective  at 
once,  but  when  administered  subcutaneously  the  serum  is  absorbed 
only  very  slowly  (Morgenroth) .  As  the  intravenous  administration 
apparently  produces  more  pronounced  side  effects  than  the  subcu- 
taneous injection  (Tachau),  it  is  perhaps  of  practical  importance  that 
the  antitoxin  is  absorbed  decidedly  more  rapidly  when  injected  intra- 
muscularly than  when  injected  subcutaneously  (Morgenroth) . 

The  curative  effects  of  antidiphtheritic  serum  are  due  to  its  power 
not  only  of  protecting  the  nervous  system  from  further  absorption 
of  the  toxins  but  also  of  neutralizing  them  in  the  tissues  where  the 
bacilli  are  multiplying  and  manufacturing  their  toxins.  These  bacilli 
cause  their  local  effects,  such  as  the  formation  of  membranes,  with 
the  aid  of  their  toxins,  which  cause  the  damage  to  the  neighboring 
tissues,  as  a  result  of  which  a  favorable  culture-medium  is  prepared 
for  the  further  multiplication  of  the  bacilli.  As  the  antitoxin  neutra- 
lizes the  toxins  in  the  tissues,  the  bacilli  are  deprived  of  these  weapons, 
and  in  this  fashion  is  explained  its  favorable  action  on  the  local  infec- 
tion, which  is  usually  rapidly  checked  by  the  serum  injection,  so  that, 
under  the  influence  of  the  natural  curative  powers  of  the  body,  it 
promptly  clears  up.  This  prevention  of  the  multiplication  of  the 
bacilli  and  of  the  manufacture  of  their  toxins,  then,  secondarily  aids 
in  bringing  about  the  disappearance  of  the  nervous  symptoms,  the 
fever,  etc.,  just  as  is  the  case  when  diphtheria  is  treated  locally  by 
caustic  agents  as  advised  by  Loeffler. 


558  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

The  strength  of  the  antidiphtheritic  serum  is,  like  that  of  other  sera,  ex- 
pressed in  immunity  units,  a  unit  being  that  amount  of  serum  which  in  vitro  will 
detoxicate  for  guinea-pigs  a  certain  amount  of  standard  toxin.  According  to  the 
German  Pharmacopoeia,  diphtheria  serum,  whicli  may  be  preserved  by  the  addi- 
tion of  phenol  or  creosol,  must  contain  at  least  300  immunity  units  per  cubic 
centimetre.  Sera  of  high  potency  contain  over  500  such  units  per  cubic  centi- 
metre. As  a  rule,  1000-6000  units  should  be  injected,  but  in  severe  cases  much 
larger  doses  should  be  given.  For  prophylactic  treatment  500  units  are,  as  a 
rule,  sufficient.  A  dried  antitoxin  is  also  obtainable,  which  contains  no  anti- 
septics and  must  contain  at  least  5000  immunity  units  per  gramme. 

BIBLIOGRAPHY 

Berghaus:   Zentralbl.  f.  Bakt.,  vol.  48,  p.  450;  vol.  49,  p.  281. 

Comby:   Arch  de  med.  des  enfants,  1904  and  1906. 

Marx :   Ztschr.  f.  Hyg.,  1901,  vol.  38. 

Meyer,  Fritz :   Arch,  f .  exp.  Path.  u.  Pharm.,  1909,  vol.  60. 

Meyer  u.  Ransom:  Arch,  de  Pharmacodyn.,  1905,  vol.  15. 

Morgenroth:   Ther.  Monatsh.,  1909,  January. 

Tachau:  Ther.  der  Gegenw.,  1910,  August. 

BACTERIOLYSINS 

When,  instead  of  the  soluble  metabolic  products  of  bacteria,  atten- 
uated or  killed  bacteria  are  used  to  produce  immunity,  the  immune 
sera  acquire  the  power  of  acting  specifically  on  the  bacteria  in  ques- 
tion. In  this  fashion  it  is  possible  to  obtain  bacteriolytic  sera,  as  was 
first  shown  by  Pfeiffer  for  the  cholera  vibriones. 

Guinea-pigs  injected  with  a  lethal  quantity  of  these  vibriones  die  with 
symptoms  similar  to  those  of  the  algid  stage  of  cholera,  and  very  active  vibriones 
are  found  in  the  peripheral  cavities.  If,  however,  such  animals  be  injected 
with  a  sufficient  dose  of  an  immune  serum  obtained  from  another  animal,  ren- 
dered immune  by  the  injection  of  non-lethal  doses  of  these  bacteria,  they  do  not 
die,  and  their  peritoneal  fluid  contains  vibriones  which  are  altered  in  their 
form  and  in  their  behavior  to  staining  agents,  and  it  is  possible  actually  to  see 
"  how  their  bodies  pass  into  solution  in  this  exudate." 

The  mechanism  of  this  phenomenon  has  been  explained  by  experi- 
ments in  vitro  (Metschnikoff)  as  follows :  Bacteriolysis  occurs  in  vitro 
only  when  fresh  immune  serum  is  brought  in  contact  with  the  bacteria, 
while  such  serum  loses  its  specific  powers  when  kept  for  a  long  time 
or  when  heated  to  60°  C.,  but  regains  it  when  the  fresh  serum  of 
normal  adults  is  added.  This  indicates  that  bacteriolysis  results  from 
the  combined  action  of  two  substances,  one  of  which  is  present  in  the 
normal  serum  of  non-immunized  animals,  but  is  very  unstable.  On 
the  other  hand,  the  specific  component  of  the  bacteriolysin,  which  is 
present  only  in  the  serum  of  the  immunized  animals,  is  more  stabile 
and  resistant  to  heating. 

Of  bactericidal  sera  we  have  thus  far  antistreptococcal,  anti- 
meningococcal,  antipneumococcal,  antityphoid,  and  anticholeraic  sera 
and  many  others,  but  their  practical  value  is  still  sub  judice. 

BIBLIOGRAPHY 

Metschnikoff :  Ann,  de  PInst.  Pasteur,  1895. 

Pfeiffer:  Deut.  med.  Woch.,  1894,  and  Ztschr.  f.  Hyg.,  1894. 


BACTERIOLYSIS  AND  HAEMOLYSIS  559 

HAEMOLYSIS 

The  studies  of  bacteriolysis  have  led  to  the  clearing  up  of  another 
biologically  important  phenomenon,  that  of  haemolysis.  Just  as  specific 
antigens,  the  bacteriolysins,  are  formed  in  the  body  after  injection 
with  the  antigens  of  the  bacterial  bodies,  so  also  the  sera  of  animals 
injected  with  other  heterologous  blood-cells  acquire  the  power  of 
acting  specifically  on  and  of  dissolving  these  cells.  Thus,  the  injection 
of  heterologous  blood-cells  causes  the  production  of  hsemolysins. 
For  example,  if  a  guinea-pig  be  injected  with  a  rabbit's  blood,  its 
serum,  which  normally  does  not  haemolyze  rabbit 's  blood-cells,  becomes 
hsemolytic  for  these  cells.  Such  a  hsemolytic  serum  becomes  ineffective 
when  heated  to  55°-60°,  but  may  be  reactivated  by  the  addition  of 
fresh  normal  rabbit  or  guinea-pig  serum.  As  was  first  recognized 
by  Bordet,  haemolysis  also  is  due  to  the  combined  action  of  a  thermo- 
labile  normal  constituent  of  the  blood  and  a  thermostable  antibody, 
whose  formation  results  from  the  injection  of  a  heterogeneous  blood. 
Normally  the  serum  of  many  species  of  animals  is  luemolytic  for  cer- 
tain heterologous  bloods,  so  that  without  any  preparatory  treatment 
they,  hEemolyze  them. 

Haemolysis  results  from  the  hasmolysin  attracting  to  itself  the  anti- 
gen contained  in  the  red  cells  and  thus  causing  the  destruction  of  their 
structure.  It  goes  without  saying  that  haemolysis  may  also  result  from 
pharmacological  actions  of  a  very  different  sort,  if  only  these  actions 
are  exerted  upon  integral  constituents  of  the  cell  body.  Examples 
of  this  are  the  haemolysis  produced  by  substances  which  dissolve  the 
lipoids  which  form  a  portion  of  the  body  of  the  blood-corpuscles, — for 
example,  that  caused  by  saponin  or  by  chloroform,  ether,  etc.  The 
hagmolysis  produced  by  hypotonic  salt  solutions,  which  cause  destruc- 
tion of  the  cells  as  a  result  of  the  inhibition  of  water,  may  also  be 
mentioned. 

The  thermolabile  substance  present  in  the  serum,  the  cooperation  of  which 
is  essential  for  haemolysis,  is  probably  derived  from  the  leucocytes,  being  either 
secreted  by  them  or  set  free  when  they  die.  Thus  far  there  is  no  uniformity  in 
the  conceptions  of  the  manner  in  which  these  two  substances  act  together  in  bac- 
teriolysis and  haemolysis.  According  to  Bordet's  views,  both  substances  act 
directly  on  the  cells,  but  the  substance  present  in  normal  serum,  named  by  him 
cytase,  can  produce  lysis  only  if  the  specific  substance  formed  during  immuni- 
zation, named  by  him  "  substance  sensibilitrice,"  has  acted  on  the  cells  in  a 
manner  comparable  to  that  in  which  mordants  prepare  fabrics  for  dye-stuffs. 

Ehrlich,  on  the  other  hand,  was  able  to  show  that  the  stable  specific  sub- 
stances, but  not  the  thermolabile  ones,  the  complement,  may  be  made  to  combine 
with  susceptible  red  cells  and  thus  be  removed  from  the  serum.  He  consequently 
assumes  that  the  substance  formed  during  immunization,  named  by  Pfeiffer  the 
immune  substance  and  by  Ehrlich  amboceptor,  combines  with  the  blood-cells  but 
by  itself  cannot  produce  lysis.  It  is  only  when  it  combines  with  the  complement 
that  a  substance  is  formed  which  combines  with  the  cells  and  dissolves  them. 

More  recently  Arrhenius  has  explained  the  combined  action  of  these  two 
substances  on  the  assumption  that  the  effective  compound  formed  by  the  immune 
body  and  the  complement  is  not  formed  in  the  serum,  or  else  is  not  stable  there, 
but  that  it  is  formed  only  in  the  blood-cell  when  both  substances  are  present. 


560  ETIOTROPIC  PHARMACOLOGICAL  AGENTS 

BIBLIOGRAPHY 

Arrhenius:   Ergebn.  d.  Physiol.,  1908,  p.  539. 

Bordet:   Ann.  de  1'Inst.  Pasteur,  1895. 

Ehrlich:  Gesammelte  Abhandlg.  z.  Immunitatsforschung,  Berlin,  1904. 

Sachs:   Die  Hiimolysine,  Wiesbaden,   1902. 

AGGLUTININS. — As  a  general  thing  antibacterial  immune  sera  pro- 
duce a  second  specific  effect  on  the  corresponding  bacteria,  which 
consists  in  agglutinating  them.  These  agglutinins,  which  were  dis- 
covered by  Gruber  and  Durham,  are  of  great  practical  importance, 
particularly  as  a  means  of  diagnosing  typhoid  ("Widal  reaction). 

BIBLIOGRAPHY 
Gruber  u.  Durham:  Munch,  med.  Woch.,  1896. 

PRECIPITINS. — Another  property  of  many  antibacterial  immune 
sera  is  their  power  of  precipitating  substances  obtained  from  dead 
bacteria  of  the  species  used  for  immunization  (Kraus).  The  sub- 
stances responsible  for  this  precipitation  are  known  as  precipitins, 
and  are  always  formed  when  heterologous  proteid  reaches  the  blood. 
Thus  precipitins  for  serum  albumin,  lactalbumin,  etc.,  may  be  formed. 
As  sera  thus  obtained  always  give  the  precipitate  or  cause  precipitation 
in  the  highest  dilutions  only  with  the  proteid  (the  precipitinogen) 
used  in  the  preparatory  treatment,  and  as  the  reaction  grows  weaker 
the  more  distant  the  relationship  between  the  tested  proteid  and  the 
precipitinogen,  this  biological  reaction  has  acquired  great  importance 
as  the  most  delicate  means  of  distinguishing  between  different  proteids, 
— for  example,  in  the  differentiation  between  human  and  animal  blood. 

BIBLIOGRAPHY 
Kraus:  Wien.  klin.  Woch.,  1897. 

CYTOTOXINS. — Specific  serum  may  be  prepared  not  only  against 
blood-cells  and  bacteria  but  also  for  all  possible  kinds  of  cells.  Thus, 
by  preparatory  treatment  with  spermatozoa  Landsteiner  has  obtained 
a  serum  which  paralyzes  their  movements,  and  v.  Dungern  a  specific 
serum  for  ciliated  epithelium.  These  cytotoxins  are  also  in  a  certain 
sense  specific,  being  always  most  toxic  to  those  cells  which  were  used 
in  the  preparation  of  the  serum.  These  investigations  are  mentioned 
here  because  it  appears  entirely  possible  and  probable  that  cytotoxic 
sera  may  be  used  to  cause  specific  destruction  of  or  damage  to  certain 
cells,  as,  for  example,  those  of  neoplasms. 

BIBLIOGRAPHY 

v.  Dungern:   Munch,  med.  Woch.,  1899. 
Landsteiner:    Zentralbl.  f.  Bakteriol.,   1899. 
Sachs,  H.:  Biochem.  Zentralbl.,  1903,  vol.  1. 


CHAPTER  XVIII 

FACTORS  INFLUENCING  PHARMACOLOGICAL 
REACTIONS 

Solubility. — The  old  axiom  "Corpora  non  agunt  nisi  soluta"  should 
be  corrected  by  the  addition  of  ' '  seu  solibilia, ' '  For  instance,  undis- 
solved  zinc  reacts  with  sulphuric  acid  in  the  presence  of  water  and 
is  dissolved  in  it,  but  gold,  being  insoluble,  is  inactive.  This  law  holds 
true  in  all  pharmacological  reactions,  and,  if  a  substance  or  compound 
is  completely  insoluble  in  the  body,  as  is  the  case  with  barium  sulphate, 
or  paraffin,  it  produces  no  pharmacological  effects,  but,  if  it  is  soluble 
to  start  with  or  if  it  becomes  so  as  a  result  of  interaction  with  the 
tissues,  as  is  the  case  with  sulphur,  it  can  produce  such  reactions. 

Most  of  the  chemical  antidotes  act  by  transforming  the  poisons  in  the  stomach 
and  intestines  into  insoluble — or  at  least  poorly  and  slowly  soluble — compounds, 
thus  preventing  or  at  least  retarding  their  absorption  and  their  toxic  actions. 

Adequate  Amount. — While  solubility  is  the  first  essential  for  a 
pharmacological  effect,  the  second  one  is  that  a  sufficient  quantity  of  the 
drug  shall  come  in  contact  with  the  tissues  or  organs  on  which  it  exerts 
its  actions. 

The  receptive  organs  of  the  nerves  of  taste  and  smell  react  to  immeasurably 
small  quantities  of  active  substances,  and  many  other  cells  act  to  equally  small 
amounts  of  adequate  physiological  stimulants.  As  an  example  of  this  the  reader 
is  reminded  of  the  chemically  scarcely  recognizable  and  still  efficient  epinephrin 
content  of  the  arterial  blood.  Moreover,  certain  other  substances  may,  under 
certain  conditions,  prove  toxic  in  almost  immeasurably  small  amounts,  as  is  the 
case  with  those  minute  traces  of  copper  which  are  present  in  water  distilled 
from  a  copper  vessel,  and  which  exert  a  harmful  action  on  certain  vegetable  or 
animal  cells  introduced  therein  (  p.  563). 

In  all  of  these  and  in  all  analogous  cases  where  extremely  small  quantities 
of  drugs  exert  a  physiological  activity,  it  has  been  possible  experimentally  to 
determine  the  lower  limits  and  the  conditions  for  such  activity.  They  have  nothing 
whatever  to  do  with  the  claimed  effects  of  homoeopathic  dilutions  of  drugs.  The 
claims  made  by  homoeopathy  are  based  on  no  experimental  tests,  but  only  on 
uncritical  and,  from  their  very  nature,  improbable  hypotheses. 

DIRECT  LOCAL  ACTIONS  will,  it  is  clear,  be  influenced  by  the  amount 
applied  and,  in  the  case  of  substances  already  in  solution,  the  concen- 
trations employed. 

Power  of  penetration  into  the  deeper  tissues  is  also  of  special  im- 
portance for  any  action  elsewhere  than  on  the  very  surface  of  the 
body.  Caustic  substances,  which  destroy  the  tissues,  penetrate  with 
difficulty  if  they  form  a  firm  and  insoluble  eschar,  but  more  readily 
if  the  compounds  formed  are  soft  or  fluid  (see  Caustics,  p.  491).  In 
general,  lipoid-soluble  substances  penetrate  more  readily  than  lipoid- 
36  561 


562  FACTORS  AFFECTING  DRUG  ACTIONS 

insoluble  ones,  and  of  these  latter  the  readily  diffusible  more  readily 
than  those  which  diffuse  with  difficulty.  This  last  rule,  it  is  clear, 
holds  good  for  the 

ABSORPTION  OP  DRUGS  FROM  THE  CIRCULATING  BLOOD  by  cells  lying 
at  a  distance  from  the  original  point  of  absorption. 

The  concentration  of  a  drug  in  the  blood,  which  determines  its 
quantitative  distribution  in  the  various  cells  and  organs,  depends  on 
the  relative  rapidity  of  its  absorption  and  of  its  elimination  or  destruc- 
tion. A  drug  reaches  the  circulation  most  rapidly  and  to  the  full 
amount  of  the  dose  administered  when  it  is  injected  intravenously — 
in  the  case  of  gases  when  it  is  inhaled — and  almost  as  rapidly  when 
injected  intramuscularly ;  but  decidedly  more  slowly,  and  almost  never 
in  its  entire  amount,  when  it  is  injected  into  the  subcutaneous  tissues, 
for  a  portion  of  it  is  absorbed  and  more  or  less  tenaciously  retained 
by  them.  Drugs  enter  the  blood  most  slowly  and  least  completely 
through  the  mucous  membranes,  and  of  these  the  mucous  membranes 
of  the  stomach  and  of  the  bladder  are  almost  impermeable  for  sub- 
stances not  soluble  in  fats.  When  absorbed  from  the  intestines,  drugs 
first  pass  into  the  liver,  where  they  meet  with  a  new  barrier,  many  of 
them  being  transformed  chemically  by  this  organ,  while  others  are 
absorbed  and  retained  by  it,  at  any  rate  for  a  time. 

If  the  elimination  through  the  stomach,  intestines,  or  lungs,  or  if 
the  distribution  of  the  drug  keep  pace  with  its  absorption,  its  concen- 
tration in  the  blood  can  never  become  high,  and  in  the  case  of  many 
substances,  such  as  curare,  if  they  be  administered  orally,  the  concen- 
tration in  the  blood  never  attains  an  adequate  or  threshold  value. 
In  case  the  normal  active  elimination  be  pathologically  diminished,  for 
example  by  renal  insufficiency,  it  is  possible  that  an  unexpectedly  high 
concentration  of  the  drug  in  the  blood  may  be  attained  so  that  a 
correspondingly  pronounced  pharmacological  or  toxic  action  results. 

Distribution. — With  a  certain  concentration  of  the  drug  in  the 
blood,  however,  it  (the  drug)  is  by  no  means  equally  distributed 
between  all  the  organs  and  cells,  but,  according  to  their  particular 
physical  or  chemical  affinity  for  the  drug,  it  is  absorbed  by  them  in 
different  amounts  and  with  varying  rapidity.  Consequently  the  final 
distribution  of  a  drug  throughout  the  body  depends  also  on  the  rate 
at  which  it  enters  into  the  various  tissue  fluids.  If  the  whole  quantity 
enters  these  at  one  time,  the  more  avid  cell  A  will,  in  comparison  with 
the  less  avid  cell  B,  attract  to  itself  relatively  more  of  the  drug  than 
will  be  the  case  when  the  drug  enters  these  fluids  only  gradually  and 
consequently  circulates  around  in  these  fluids  for  a  longer  time  but  in 
higher  dilution.  If  A  be  not  only  the  more  avid  but  also  the  specifi- 
cally susceptible  cell,  and  B  the  less  avid  and  relatively  insusceptible 
cell,  the  pharmacological  effect  is  more  pronounced  when  the  whole 
dose  is  given  at  once ;  but,  if  the  more  avid  cell  be  the  less  susceptible 


SIZE  OF  DOSE  563 

one,  then  small,  rapidly  repeated  doses  will  be  the  most  effective. 
While  it  is  not  possible  to  predict  for  every  drug  how  it  will  behave  in 
this  respect,  it  is  possible  to  determine  this  empirically  for  any  given 
one  (Beinaschewitz). 

Except  in  the  case  of  the  locally  acting  caustics  and  irritants,  the 
quantity  of  the  drug  which  actually  acts  on  the  specifically  susceptible 
cells,  as  a  rule,  forms  only  an  immeasurably  small  portion  of  the  dose 
administered.  After  absorption  a  drug  is  distributed  by  the  blood 
and  lymph  throughout  the  whole  body,  and,  according  to  its  physico- 
chemical  properties,  is  retained  and  stored  up  by  cells  of  the  most 
different  sorts,  either  mechanically  or  by  capillary  adhesion  or  by 
entering  into  solution  or  chemical  combination  with  the  cellular  con- 
stituents. Cumulation — that  is  to  say,  the  absorption  and  retention 
of  relatively  large  amounts  of  the  drug  by  certain  cells  and  cell  com- 
plexes— renders  possible  the  elective  action  of  even  extremely  small 
doses.  For  example,  1  mg.  of  digitoxin  distributed  throughout  a  body 
weighing  70  kilos  gives  a  dilution  of  one  to  70  million,  a  concentration 
which  is  far  from  high  enough  to  exert  any  appreciable  action  on  the 
cardiac  muscle,  were  it  not  for  the  fact  that  this  poison  is  absorbed 
and  retained  by  the  cardiac  muscle  more  than  by  any  other  cells,  and 
consequently  may  attain  in  it  an  adequate  concentration,  just  as  copper 
salts  in  an  extremely  dilute  solution  (1  mg.  in  100  1.)  are  absorbed 
and  accumulated  by  algae  in  far  greater  concentration  (Devoux). 

BIBLIOGRAPHY. 

Beinaschewitz,  F. :  Therap.  Monatshefte,  October,  1910. 
Devoux:   Compt.  rend.  Academic  des  Sciences,  vol.  131,  p.  717. 
Straub,  W.:  Arch,  di  Fisiol.,  1903,  vol.  1,  p.  55. 

RELATIONSHIP  BETWEEN  THE  SIZE  OF  THE  DOSE  AND  THE  INTENSITY 
OF  THE  PHARMACOLOGICAL  ACTION. — While  the  absorption  and  the  suf- 
ficient storing  up  of  a  drug  in  certain  cells  and  organs  are  naturally 
a  necessary  preliminary  condition  for  its  elective  pharmacological 
action  thereon,  it  can  by  no  means  be  used  as  a  measure  therefor,  for 
many  cells  may  accumulate  a  substance  in  considerable  amounts  with- 
out being  harmed  or  functionally  disturbed  (Straub}.  Examples  of 
this  are  the  intra-vital  staining  methods  used  in  histology  and  the 
forensically  important  accumulation  of  many  poisons  in  the  liver, 
kidney,  spinal  marrow,  etc. 

The  amount  of  the  drug  which  finally  becomes  effective  determines 
the  actual  degree  of  the  pharmacological  action,  but  this  amount  and 
the  effect  produced  are  by  no  means  directly  proportional,  for  so  long 
as  it  remains  below  a  certain  amount,  the  threshold  value,  no  appre- 
ciable effect  at  all  is  produced,  for  very  slight  chemical  disturbances 
are  borne  by  living  cells  without  appreciable  alterations  of  their  func- 
tions, just  as  they  support  the  daily  and  hourly  variations  of  osmotic 
tension,  of  temperature,  and  of  other  factors  in  their  normal  environ- 


564  FACTORS  AFFECTING  DRUG  ACTIONS 

ment.  Consequently  the  ineffective  or  just  effective  doses  must  be 
subtracted  from  the  different  doses  administered  in  order  to  determine 
the  true  ratio  between  them. 

If,  as  is  always  necessary  in  the  case  of  medicinal  administration, 
that  portion  of  the  drug  which  is  retained  in  other  organs,  and  which 
does  not  reach  the  insusceptible  organs  at  all,  be  also  included  in  the 
"threshold  dose,"  the  difference  becomes  still  greater. 

For  example,  if  for  a  normal  adult  the  empiric  threshold  dose  of  digitoxin 
be  about  0.9  mg.,  —  that  is,  if  this  be  the  dose  which  produces  a  hardly  appreciable 
effect,  —  the  amounts  of  digitoxin  which  actually  come  into  action  when  1  mg. 
and  when  2  mg.  are  administered  may  be  stated  to  be  in  the  proportion  (  1.0  minus 
0.9)  to  (2.0  minus  0.9),  i.e.,  0.1  to  1.1  =  1  to  11.  Consequently,  while  the  pharma- 
cological effect  of  1.0  mg.  may  be  just  appreciable,  the  dose  of  2.0  mg.,  which  is 
apparently  only  twice  as  large,  may  be  unexpectedly  severe  and  perhaps  dangerous. 
This  example  is  not  a  hypothetical  one,  but  is  the  result  of  experiments  made  by 
Koppe  on  himself. 

Unfortunately,  we  have  no  methods  by  which  the  intensity  of 
pharmacological  actions  may  be  directly  measured  except  in  the  case 
of  certain  blood  poisons,  in  which  the  intensity  of  action  may  be 
estimated  by  the  extent  to  which  the  red  cells  lose  their  coloring 
matter.* 

The  final  amount  of  haemolysis  caused  in  like  suspensions  of  blood- 
cells  by  different  quantities  of  a  haemolytic  agent  expresses,  in  per- 
centages, the  functional  relationship  between  the  amount  of  the 
haemolytie  agent  and  the  intensity  of  its  action. 

Further,  the  rapidity  with  which  a  certain  determinable  effect  (for 
example,  the  cessation  of  respiration  in  fish  or  the  death  of  bacteria) 
occurs  after  a  certain  dosage  may  serve  as  an  indirect  measure  of  its 
activity.  In  such  case  the  degree  of  activity  is  the  reciprocal  of  the 
rapidity  with  which  the  action  is  produced.  Using  such  methods,  it 
has  been  shown  that,  as  a  rule,  the  rapidity  with  which  toxic  effects 
are  produced  increases  much  more  rapidly  than  do  the  corresponding 
doses,  calculated  after  subtraction  of  the 


In  Fig.  62  the  curve  represents  the  intensity  of  the  haemolytic  action,  and 
in  Fig.  63  the  unbroken  curve  represents  the  time  required  for  the  various  concen- 
trations of  ether  to  narcotize  email  fishes,  and  the  broken  curve,  which  is  the 
reciprocal  of  the  time  curve,  represents  the  intensity  of  the  narcotizing  action. 
Both  of  these  curves,  the  one  indicating  the  percentage  of  haemoglobin  dissolved 

*  This  method,  however,  assumes  that  with  partial  haemolysis  each  red 
blood-cell  gives  up  a  corresponding  portion  of  its  haemoglobin,  —  that  is,  is  partially 
poisoned.  However,  up  to  the  present  it  is  uncertain  whether  this  is  actually 
the  case,  or  whether  in  the  partial  haemolysis  of  a  given  number  of  red  cells  a 
certain  portion  of  them  are  completely  haemolyzed  while  the  rest  retain  their 
normal  quantity  of  coloring  matter.  As  a  general  thing,  this  last  is  assumed 
to  be  the  case,  although,  in  view  of  the  regular  curves  of  haemolysis  obtained  in 
such  experiments,  this  is  hard  to  understand.  According  to  unpublished  experi- 
ments of  Handowski,  partial  haemolysis  is  the  expression  of  the  different  resisting 
powers  of  the  different  blood-corpuscles  in  a  certain  quantity  of  blood,  and  it 
appears  that  the  youngest  blood-cells  are  the  more  resistant  to  haemolytic  sera 
and  those  haemolysins  which  act  on  the  lipoids. 


SIZE  OF  DOSE 


565 


out  of  a  given  number  of  erythrocytes  by  increasing  amounts  of  saponin  and 
the  other  the  intensity  of  the  narcotic  action  of  increasing  amounts  of  ether,  show 
the  rapid  augmentation  of  the  toxic  action.  The  efficiency  of  disinfectants  increases 
just  as  rapidly  in  proportion  to  the  increase  of  their  concentration,  the  time 
needed  for  the  killing  of  bacteria  being  indirectly  proportional  to  the  efficiency 
of  different  concentrations  (Paul,  Birstein,  u.  Reuss). 


100 


180 


540 

i 


r 

So 


<tt  0.2  03  0.5  0.75  I 


FIG.  62. 


160 
140 
120 
100 
80 
60 
40 
20 

n 

! 

. 

i 

: 

/ 

'' 

V 

/ 

\ 

/ 

> 

\ 

,.-- 

x" 

^v 

— 

—  •  — 

'/o  VooSAPONIN 

TO  /oaf.  CM. 

BLOOD 


TIME.  CURVE 


~  ~/NTE.NSITY-(RECIPROCAL  OF  TIME.  CURVE.) 
Fio.  63. 


This  means  that  cells  acted  upon  and  to  some  extent  affected  by 
a  certain  amount  of  a  toxic  substance,  or  certain  portions  of  them 
not  yet  affected  and  still  functioning  normally,  become  less  and  less 
resistant  and  more  and  more  susceptible  to  increasing  amounts  of  the 
same  substance,  until  finally  the  smallest  increase  is  sufficient  to  pro- 
duce the  maximum  effect.  This  is  apparently  almost  the  converse  of 
the  ratio  between  the  intensity  of  perception  and  increasing  stimuli 
as  expressed  in  the  law  of  Weber  and  Fechner.  Fig.  64  expresses 
this  contrast  graphically. 


20 


15 


10 


12345         10         15        20 

-DEGREE  OF       INTENSITY 

SENSIBILITY  OF  EFFECT 

FIQ.  64. 


In  many  cases  the  effect  produced  by  very  small  doses  is  the  direct 
opposite  of  that  produced  by  larger  ones,  the  smaller  doses  stimulating 
certain  vital  phenomena  while  larger  ones  inhibit  them,  just  as  moder- 
ate heating  stimulates,  while  overheating  first  narcotizes  and  finally 
kills  living  cells  (H.  Meyer).  In  animal  pharmacology  we  meet  with 


566  FACTORS  AFFECTING  DRUG  ACTIONS 

this  reversal  of  the  effect  in  the  case  of  the  narcotics  of  the  central 
and  peripheral  nervous  system,  in  connection  with  many  central  ex- 
citants,— for  example,  strychnine,  HCN,  and  H2S, — and  with  many 
so-called  alternatives, — for  example,  arsenic,  phosphorus,  etc.  Vege- 
table pharmacology  also  offers  many  similar  examples, — for  instance, 
the  activity  of  yeasts  may  be  quite  generally  augmented  by  minimal 
amounts  of  different  inorganic  substances  which  in  large  amounts 
depress  or  paralyze  them  (Schulz),  and  the  same  has  long  been  known 
of  the  effects  of  such  substances  on  bacteria  and  moulds. 

BIBLIOGRAPHY 

Koppe:  Arch.  f.  exp.  Path.  u.  Pharm.,  1875,  vol.  3,  p.  274. 
Meyer,  H.:   Munch,  med.  Woch.,   1909,  No.  31. 
Paul,  Birstein  u.  Reuss:   Biochem.  Ztschr.,  1910,  vol.  29,  p.  202. 
Schulz:  Pttiiger's  Arch.,  1888,  vol.  42,  p.  517. 

PHARMACOLOGICAL  ACTIONS  INFLUENCED  BY  THE  FUNCTIONAL  CON- 
DITION OF  THE  ORGANS. — Another  much  larger  and  more  important 
group  of  factors  affecting  the  pharmacological  action  of  various  drugs 
and  the  whole  picture  produced  by  them  is  found  in  the  composition 
and  structure  and  the  momentary  conditions  of  those  organs  and  cells 
which  are  directly  acted  upon  by  the  drugs  in  question.  In  this  fashion 
differences,  which  are  otherwise  unrecognizable,  may  betray  themselves 
by  very  striking  differences  in  pharmacological  reactions,  and  these, 
in  even  the  most  simple  of  experiments,  may  lead  to  apparently  contra- 
dictory results. 

A  well-known  example  of  this  is  the  effect  of  caffeine  in  frogs,  in  which 
certain  earlier  investigators  observed  only  a  reflex  tetanus  similar  to  that  pro- 
duced by  strychnine,  while  others  noted  only  a  muscular  rigor  which  was  quite 
independent  of  any  action  on  the  spinal  cord.  Consequently  their  explanations 
of  the  actions  of  caffeine  were  entirely  different.  One  group  of  these  investi- 
gators, however,  had  used  only  Rana  esculenta,  while  the  others  had  used  R.  tem- 
poraria,  and  later  investigations  showed  that  in  these  two  species  of  frogs  both 
of  these  pharmacological  actions  were  produced,  but  that  in  one  species  the 
augmentation  of  reflex  excitability  and  in  the  other  the  muscular  rigor  was 
more  readily  induced.  Consequently,  when  the  pharmacological  action  developed 
rapidly,  only  one  of  these  effects  was  apparent  and  concealed  the  other 
( Schmiedeberg) . 

Such  differences  in  susceptibility  are  observed  not  only  between 
the  muscles  of  related  or  entirely  unrelated  species,  but  also  between 
the  muscles  of  a  single  individual.  Thus,  the  more  excitable  muscles, 
which  are  more  generally  active  in  daily  life,  react  to  pharmacological 
agents  more  rapidly  and  more  decidedly  than  the  more  sluggish  and 
less  used  ones.  Thus,  in  birds  of  flight  the  leg  muscles  are  less  sus- 
ceptible than  the  much  used  wing  muscles,  while  the  contrary  is  true 
in  those  birds  which  do  not  fly;  and  in  chronic  lead  poisoning  the 
muscles  of  the  hand  and  forearm,  which  are  those  most  used  in  ordin- 
ary labor,  are  the  first  to  be  affected  by  paralysis  (Teleky}.  Even 
greater  differences  in  the  effect  of  drugs  may  be  observed  in  muscles 


CONDITION  OF  THE  ORGANS  567 

with  normal  tone  and.  those  in  which  the  tone  is  pathologically  aug- 
mented or  depressed.  Thus,  the  gravid  uterus,  whose  muscle-fibres 
are  more  stretched  than  those  of  the  non-gravid  organ  and  which  conse- 
quently are  more  susceptible  to  contractile  stimuli,  ordinarily  contract 
when  the  mixed  hypogastric  nerve,  which  contains  both  exciting  and 
inhibitory  fibres,  is  stimulated,  while  the  opposite  effect  is  produced 
in  the  non-gravid  organ.  Pilocarpine  and  epinephrin,  like  the  electric 
stimulation  of  this  nerve,  in  the  one  condition  cause  the  uterus  to  con- 
tract and  in  the  other  to  relax  (Cushny).  What  has  been  stated  above 
for  the  muscle-cells  holds  good  also  for  all  the  other  cells  of  the 
organism. 

Generally  one  may  assume  that  all  living  cells  will  show  the  thus 
far  inexplicable  tendency  to  maintain  a  normal  functional  mean  of 
activity  or  position,  and  that  they  will  of  their  own  accord  return  to 
it  if  forced  to  depart  from  this  mean  in  one  direction  or  the  other. 
It  is  this  self-regulating  inherited  tendency  of  cells  which  is  responsible 
for  the  permanence  of  the  individual  and  of  the  species,  and  which  is 
the  essential  cause  of  the  vis  medicatrix  naturae.  A  very  simple  and 
at  the  same  time  characteristic  and  instructive  example  of  this  is  the 
behavior  of  the  tissue  cells  in  the  presence  of  changing  osmotic  ten- 
sion. If  the  surviving  liver  be  transfused  with  hypotonic  saline  solu- 
tion, it  swells  up  slowly  as  a  result  of  the  swelling  of  the  individual 
cells,  but  if  an  isotonic  solution  be  then  transfused  it  rapidly  regains 
its  normal  size  and  condition.  In  a  similar  fashion,  under  the  in- 
fluence of  hypertonic  solutions,  it  shrinks  but  slowly,  and  regains  its 
normal  condition  very  rapidly  when  isotonic  solutions  are  transfused 
(Demoor}. 

It  would  thus  appear  that  in  living  cells  osmotic  reactions  back 
toward  the  normal  are  much  more  readily  induced  than  those  in  the 
opposite  direction.  Much  the  same  holds  good  for  the  varying  con- 
ditions of  tension  in  contractile  elements,  the  state  of  excitation  or 
tone  of  nerve  centres,  etc.  In  this  connection  the  reader  is  reminded 
of  the  powerful  action  of  the  antipyretics  on  the  pathologically  excited 
heat  centres  (p.  466),  and  of  the  power  of  digitalis  to  regulate  the 
irregularly  beating  heart  (p.  296). 

It  must  not  be  forgotten,  however,  that  in  the  case  of  many 
organs  and  functions  the  conditions  are  not  so  simple  as  in  the  above- 
mentioned  examples ;  for  normally  most  of  these  are  continually  under 
the  influence  of  a  double  antagonistic  innervation,  through  which  they 
receive  both  exciting  and  inhibiting  stimuli,  either  through  nervous 
stimulation  or  the  action  of  chemical  substances,  such  as  the  hor- 
mones. Thus,  the  intestinal  musculature  receives  exciting  impulses 
through  the  vagus  and  inhibiting  ones  through  the  sympathetic ;  conse- 
quently, if  the  intestine  be  completely  relaxed,  solely  because  it  is 
receiving  no  exciting  stimuli  through  the  vagus,  any  agent  which 
stimulates  the  vagus  produces  a  marked  effect  upon  it  and  readily 


568  FACTORS  AFFECTING  DRUG  ACTIONS 

causes  a  contraction  and  to  a  greater  degree  than  if  the  intestine  had 
originally  been  in  a  state  of  moderate  contraction.  On  the  other 
hand,  if  the  original  relaxation  had  been  due  to  powerful  inhibition 
through  the  sympathetic,  this  would  oppose  the  action  of  the  agent 
exciting  the  vagus,  and  consequently  the  effect  would  be  slighter  than 
if  the  intestine  had  been  in  a  state  of  ordinary  repose. 

BIBLIOGRAPHY 

Cushny:  Journ.  of  Physiol.,  1910,  vol.  41,  p.  235. 
Demoor:  Bull,  de  1'Ac.  r.  de  Big.,  December,  1906. 
Schmiedeberg,  J. :  Arch.  f.  exp.  Path.  u.  Pharm.,  1873,  vol.  2. 
Teleky:  Deut.  Ztschr.  f.  Nervenheilk.,  1909,  vol.  37,  p.  284. 

ANTAGONISM. — This  physiologically  antagonistic  nervous  mechan- 
ism of  all  the  vegetative  organs,  the  unstriped  muscles,  the  glands, 
and  the  circulatory  organs,  must  consequently  often  modify  the 
actions  of  those  drugs  which  act  on  this  system,  and  be  the  cause  and 
the  explanation  of  the  reciprocal  antagonism  between  those  pharma- 
cological agents  which  excite  the  activity  of  the  two  portions  of  this 
antagonistic  nervous  mechanism. 

The  antagonistic  effects  of  small  and  large  doses  of  the  same  drug  may  also 
depend  on  this  physiologically  antagonistic  innervation.  Thus,  according  to 
Schwartz,  small  doses  of  choline  excite  the  inhibiting  centres  for  the  pancreatic 
secretion,  while  large  doses  stimulate  the  secretory  nervous  organs  lying  in  the 
gland  itself.  Wertheimer  and  Lepage  state  that  just  the  opposite  is  true  for 
atropine. 

Little  is  actually  known,  and  still  less  is  understood,  of  the  antag- 
onistic effects  produced  in  the  various  organs  by  the  internal  secre- 
tions, which  may  be  looked  upon  as  physiologically  formed  pharmaco- 
logical agents.  Among  these  mention  may  be  made  of  the  partial 
antagonism  between  choline  and  epinephrin  (see  pp.  164,  188,  189).  In 
other  cases,  such  as  that  of  the  probably  antagonistic  action  of  epi- 
nephrin and  the  pancreas  hormone  on  the  liver-cells  (see  pp.  171,  419), 
we  are  entirely  in  the  dark  as  to  how  they  act,  nor  can  this  antag- 
onism be  explained  in  the  above-mentioned  manner.  When  we  en- 
deavor to  explain  the  antagonistic  actions  of  the  thyroid  hormones  and 
those  of  the  hypophysis  and  of  the  reproductive  glands,  we  are  still 
more  at  a  loss. 

There  is  no  particular  difficulty  in  understanding  the  antagonism 
between  various  drugs  and  poisons  when  this  depends  on  the  antago- 
nistic innervation  of  certain  organs.  Thus,  if  a  drug  stimulates  the 
vasodilators  it  is  clear  that  it  must  oppose  the  action  of  another  which 
stimulates  the  vasoconstrictors. 

Much  more  difficult  to  understand,  however,  is  an  antagonism  in 
which  one  drug  overcomes  the  effect  produced  by  another  one  in  the 
same  cell  or  functional  element  without  the  aid  of  any  antagonistic 
physiological  mechanism.  Here  it  is  necessary  to  differentiate  between 


DISTOXICATION  AND  ANTAGONISM  569 

two  fundamentally  different  methods  by  which  such  results  may  be 
obtained, — namely,  by  distoxication  and  by  true  physiological  antag- 
onism. 

(a)  Distoxication. — When  one  substance  chemically  changes  or 
combines  with  another, — that  is,  satisfies  its  specifically  active  affinity, 
—it  appears  to  act  antagonistically.  Such  an  action  we  speak  of  as  a 
chemical  distoxication,  examples  of  which  are  the  distoxication  of 
cyanides  and  of  nitrils  by  hyposulphites. 

Hydrocyanic  acid  and  the  nitrils,  for  example  malonitril,  are  readily  trans- 
formed by  active  sulphur  into  the  less  toxic  sulphocyanides,  and  consequently 
it  is  possible,  by  subcutaneous  or,  better,  by  intravenous  injection  of  a  solution 
of  hyposulphite,  to  rescue  animals  which  have  received  lethal  doses  of  a  cyanide 
or  a  nitril  and  which  are  already  in  the  death  struggle.  On  account  of  the  extra- 
ordinary rapidity  with  which  the  respiratory  centre  is  paralyzed  in  cyanide 
poisoning,  the  antidote  in  such  cases  must  immediately  follow  the  poison,  or 
artificial  respiration  must  be  performed  for  some  minutes,  in  order  to  overcome 
the  effects  of  this  toxic  action.  As  the  nitrils  produce  their  effects  much  more 
slowly,  their  distoxication  can  be  accomplished  after  the  lapse  of  a  considerably 
longer  period. 

In  this  case  the  antidote  penetrates  into  the  already  poisoned  cells  or  into 
their  immediate  neighborhood,  and  destroys  the  poison  absorbed  by  them,  a  fact 
which  is  of  decisive  importance  for  its  efficiency. 

Examples  of  distoxication  as  a  result  of  chemical  combination  are 
furnished  by  the  distoxication  of  free  acids  by  alkaline  carbonates,  that 
of  oxalates  by  lime  salts  (Januschke),  and  that  of  the  saponins  (Ran- 
som) and  of  the  crotalus  toxin  (Filhner)  by  cholesterin. 

When  the  combination  formed  by  the  poison  and  the  protoplasm, 
or  more  correctly  the  reacting  constituent  thereof,  is  reversible  with 
difficulty  or  not  at  all  ( for  instance,  on  account  of  its  complete  insolu- 
bility) ,  it  is  quite  clear  that  even  an  adequate  antidote,  which  is  able 
to  combine  with  the  poison,  cannot  reverse  the  toxic  reaction.  How- 
ever, in  such  case  it  may  be  possible  to  repair  the  protoplasm  by 
replacing  such  of  its  constituents  as  have  combined  with  the  toxic 
agent.  This  is  actually  what  occurs  in  the  antagonistic  action  of  lime 
salts  in  oxalate  poisoning.  When,  on  the  other  hand,  the  toxic  reac- 
tion is  readily  reversible,  as  for  example  in  chloral  or  chloroform  poi- 
soning, a  substance  which  possesses  an  avidity  for  the  toxic  substance 
equal  to  or  greater  than  that  of  the  cell  constituents  can  attract  the 
toxic  substance  to  itself  and  thus  overcome  the  poisoning  of  the  cell. 
Thus,  according  to  Nerking,  it  is  possible  to  lessen  or  overcome  a 
deep  chloroform  narcosis  by  the  intravenous  injection  of  a  lecithin 
emulsion. 

(&)  True  Antagonism. — The  antagonism  between  atropine  and 
muscarine  is  the  classic  example  of  true  physiological  antagonism, 
for  these  two  antagonistically  acting  drugs  have  no  chemical  affinities 
for  and  do  not  react  with  each  other,  but  produce  directly  opposite 
effects  upon  the  same  organic  elements. 

Nasse's  studies  of  the  action  of  poisons  on  ferments  have  given 


570  FACTORS  AFFECTING  DRUG  ACTIONS 

us  a  knowledge  of  the  simplest  type  of  this  kind  of  antagonism.  He 
found  that  the  activity  of  the  yeast  ferment,  invertin,  was  inhibited 
by  KC1  and  accelerated  by  NH4C1,  and  that  in  certain  relative  pro- 
portions these  two  substances  could  overcome  each  other's  actions; 
and  that  the  same  was  true  for  the  alkaloids  quinine  and  curarin,  the 
first  inhibiting,  the  latter  favoring,  and  the  two  together,  if  in  proper 
proportions,  leaving  unaltered  the  activity  of  this  ferment.  In  other 
words,  he  found  that  there  was  a  complete  reciprocal  antagonism  be- 
tween these  substances.  Inasmuch  as  neither  potassium  chloride  nor 
curare  enters  into  any  chemical  reaction  with  ammonium  chloride  and 
quinine  respectively,  we  are  able  to  understand  their  reciprocal  antag- 
onism only  if  we  assume  the  existence  in  the  ferment  of  a  common 
point  of  attack  for  both  of  the  antagonists,  which  is  influenced  in 
opposite  directions  when  it  combines  with  one  or  the  other  of  these. 

A  somewhat  rough  comparison  may  aid  in  elucidating  this.  Sea 
water  possesses  a  certain  conductivity  or,  in  a  physiological  sense,  ex- 
citability, which  may  be  increased  by  the  addition  of  alum  or  mark- 
edly decreased  by  that  of  alcohol,  for  the  former  is  an  electrolyte  and 
the  latter  a  non-conductor.  Either  of  these  may  be  removed  from  the 
water  by  the  addition  of  the  other,  for  the  alum  can  be  precipitated 
by  the  addition  of  alcohol  and  conversely  the  alcohol  may  be  separated 
from  the  water  by  the  addition  of  alum.  Consequently,  according  to 
the  varying  proportions  of  these  two  substances  added,  an  equilibrium 
may  be  established  in  the  sea  water  with  increased,  diminished,  or  unal- 
tered conductivity.  An  example  of  a  similar  phenomenon  closely  re- 
sembling certain  vital  phenomena  is  furnished  by  the  action  of  saline 
solutions  on  colloids,  the  salts  of  monovalent  and  bivalent  metals 
inhibiting  each  other's  power  of  precipitating  proteid  and,  according 
to  their  effective  amounts,  forcing  each  other  out  of  their  sphere  of 
activity.  An  entirely  similar  antagonism  between  the  monovalent 
and  polyvalent  metallic  ions  has  been  demonstrated  in  connection  with 
the  action  of  saline  solutions  on  living  organisms,  such  as  fundulus 
eggs,  and  muscles  and  contractile  organs  generally.* 

These  facts  compel  us  to  assume  for  the  antagonists  in  question 
a  similar  reversible  reaction, — that  is,  a  labile  combination  of  some  sort 
or  other  with  the  common  substratum  of  the  living  cells,  in  which, 
according  to  the  preponderance  of  one  or  the  other  of  the  antagonists, 
inhibition  or  excitation  of  the  cell  function  is  more  strongly  developed. 
For  such  a  hypothetical  phenomenon  there  actually  exists  an  exactly 
investigated  example  in  the  behavior  of  oxygen  and  carbon  monoxide 
in  the  red  cells.  Here  oxygen  is  the  stimulating  or  exciting  agent  and 
carbon  monoxide  the  inhibiting  or  depressing  one,  and,  while  they  do 
not  react  with  each  other,  they  both  possess  a  similar  but  quantita- 

*  In  this  connection  special  mention  should  be  made  of  the  reciprocal 
antagonism  between  K  and  Na  ions,  which,  so  long  as  their  relative  proportion 
be  about  1  to  17,  are  non-toxic  to  the  fundulus,  but  which,  if  this  relative  proportion 
be  altered  appreciably,  no  longer  compensate  each  other  and  become  toxic  ( Loeb ) . 


ANTAGONISM  571 

tively  very  different  affinity  for  haemoglobin,  and  consequently,  accord- 
ing to  the  relative  amounts  present,  are  able  to  force  each  other  out  of 
their  combinations  with  haemoglobin.  It  is  for  this  reason  that  it 
is  possible,  by  supplying  oxygen  freely,  to  restore  to  a  normal  con- 
dition blood  which  is  actually  saturated  with  carbon  monoxide,  pro- 
vided only  that  the  poisoning  has  not  already  persisted  so  long  as  to 
bring  about  the  death  of  the  erythrocytes.  Under  such  conditions, 
however,  the  removal  of  the  carbon  monoxide  takes  place  slowly  and 
with  difficulty,  for  its  affinity  to  haemoglobin  is  200  times  as  great  as 
that  of  oxygen,  and  consequently  the  feeble  affinity  of  the  oxygen  mole- 
cules must  be  compensated  for  by  their  number, — that  is,  by  a  larger 
amount  and  higher  concentration.  For  this  reason  inhalation  of  oxy- 
gen can  by  no  means  always  rescue  the  victims  of  coal  gas  poisoning, 
for  the  removal  of  the  carbon  monoxide  requires  so  long  a  time  that 
in  the  interim  the  brain  and  the  heart  may  succumb  to  asphyxia. 

In  the  above  we  have  touched  on  a  question  of  fundamental  im- 
portance, the  question  as  to  the  possibility  of  an  absolute  reciprocal 
antagonism.  This  possibility  has  been  repeatedly  denied  on  the 
ground  that,  while  it  is  possible  to  bring  about  paralysis  in  a  stimu- 
lated organism,  it  is  not  possble  to  bring  about  stimulation  in  a 
paralyzed  one,  and  that  the  paralyzing  poison  under  all  conditions 
will  maintain  the  upper  hand.  In  a  static  sense  this  is  correct;  but 
the  static  condition  in  a  cell  poisoning  holds  good  only  for  the  irre- 
versible toxic  actions  of  colloids,  toxins,  and  certain  metallic  ions, 
while  in  almost  all  other  acute  poisonings  the  combination  between 
poison  and  protoplasm  is  a  dissoluble  one,  so  that  the  cell  may  be 
restored  again  and  the  poison  washed  out  from  it  if  it  be  bathed 
with  blood  which  has  been  freed  of  the  poison.  If  then  the  indifferent 
pure  blood  be  replaced  by  one  containing  an  antagonistic  drug, — that 
is,  one  possessing  a  similar  affinity  for  the  affected  elements  of  the 
cells, — the  original  poison  must  be  forced  out  from  its  combinations 
and  the  distoxication  be  accelerated,  while  at  the  same  time  the  stimu- 
lating antagonistic  effect  of  the  antidote  will  produce  its  action. 

A  very  instructive  example  of  such  an  antagonistic  rivalry  between 
two  substances  is  furnished  by  the  effect  of  lime  salts  in  combating 
the  narcotic  effects  of  magnesium  salts  (Meltzer  and  Auer)  (see  p. 
110).  In  a  more  general  form  this  reciprocal  antagonism  between 
the  four  cations  Ca',  Mg',  Na',  and  K'  is  more  or  less  clearly  evidenced 
in  living  organisms,  for  the  tissues  apparently  can  maintain  their  nor- 
mal functions,  particularly  their  normal  excitability,  only  when  these 
cations  are  present  in  the  tissues  in  their  correct  relative  proportions 
(Loeb,  Melfzer) .  It  is  probable,  also,  that  the  fact  that  the  previously 
mentioned  toxicity  for  low  forms  of  life,  exhibited  by  the  minute 
amounts  of  copper  present  in  distilled  water,  may  be  abolished  by  the 
addition  of  a  small  amount  of  NaCl,  is  to  be  explained  in  a  similar 
fashion  (Bullot,  Loeb). 


572  FACTORS  AFFECTING  DRUG  ACTIONS 

The  reciprocal  antagonism  between  atropine  and  pilocarpine  and 
muscarine  is  also  to  be  attributed  to  similar  factors.  Here,  too,  the 
affinity  of  one  of  the  toxic  agents  for  the  cell  protoplasm  and  perhaps 
also  its  power  of  penetrating  into  it  is  greater  than  that  of  the  other, 
just  as  is  the  case  with  carbon  monoxide  and  oxygen,  and  consequently 
the  antagonistic  effect  may  be  looked  upon  as  dependent  on  the  rela- 
tive toxic  affinities  and  the  effective  quantities  and  the  rates  of  reac- 
tions of  the  different  drugs. 

In  this  view  of  these  phenomena  it  is  assumed  that  the  antagonistic 
drugs  possess  a  common — that  is,  exactly  the  same — seat  of  action  in 
the  organs;  but,  as  a  matter  of  fact,  this  is  absolutely  incapable  of 
experimental  proof,  and  can  be  logically  deduced  only  in  those  cases 
where  strict  reciprocal  antagonism  has  been  demonstrated.  However, 
there  is  another  possible  explanation  for  such  antagonism, — namely, 
that  the  paralyzing  drug  acts  on  the  cells  at  a  less  peripheral  point 
than  does  the  stimulating  one.  In  such  case,  on  the  one  hand,  the 
paralyzing  drug  would  block  the  path  for  the  stimuli  arriving  through 
the  nerves  to  such  a  degree  that  these  stimuli  would  no  longer  reach 
the  more  peripheral  elements  with  sufficient  strength  to  produce  exci- 
tation, while,  on  the  other  hand,  as  the  stimulating  drug  renders  these 
last-mentioned  elements  more  excitable,  it  would  in  turn  be  able  to 
render  them  susceptible  to  previously  ineffective  stimuli.  If  the  de- 
pression or  paralysis — that  is,  the  blocking — is  so  complete  that  abso- 
lutely no  stimulating  impulses  can  pass,  the  stimulating  antagonist 
is  ineffective,  and  consequently  in  such  case  one  may  in  a  strict  sense 
speak  only  of  a  one-sided  or  pseudo  antagonism.  This  would  appear 
to  be  the  case,  for  example,  with  the  antagonism  between  curare  and 
physostigmine,  and  it  is  probable  that  the  antagonism  between  cerebral 
and  spinal  stimulants  and  depressants  rests  upon  a  similar  basis. 
For  example,  morphine  narcosis  may  be  partially  counteracted  by 
atropine,  and  atropine  excitation  by  morphine.  A  similar  partial  an- 
tagonism exists  between  such  narcotic  drugs  as  chloral  hydrate  and 
alcohol,  and  such  stimulating  ones  as  caffeine,  strychnine,  and  cocaine. 

Probably  in  all  these  cases  we  are  never  dealing  with  a  complete  paralysis 
but  only  with  a  great  weakening  or  obstruction  of  the  conduction  of  excitation, 
BO  that  the  normal  impulses  are  weakened  or  retarded  on  their  way  to  the  motor 
ganglion-cells  and  consequently  are  unable  to  produce  in  them  the  essential 
discharge  of  nervous  energy.  The  antagonistic  stimulating  drug  may  then  pos- 
sibly so  lower  the  threshold  for  stimuli  in  the  motor  neuron  or  in  the  interposed 
switching  stations  that  the  abnormally  weakened  centripetal  stimuli  are  suffi- 
cient to  bring  about  the  necessary  discharge  of  energy.  This  conception  is  sup- 
ported by  the  fact  that  the  receptive  organs  of  the  spinal  reflex  arc  are  always 
more  rapidly  and  markedly  affected  by  narcotic  drugs  than  are  the  motor  ones, 
so  that  the  latter  may  still  retain  an  almost  normal  excitability  and  yet  remain 
at  rest  because  they  do  not  receive  adequate  stimuli  from  the  inhibited  receptive 
tracts. 

BIBLIOGKAPHY 
Baum,  H.:  Diss.,  Rostock,  1892. 

Bullot:  Univ.  of  Calif.  Publ.  Physiol.,  1904,  vol.  1,  p.  199. 
Fiihner:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  63,  p.  383. 


IMMUNITY  573 

Januschke:   Arch.  f.  exp.  Path.  u.  Pharm.,  1909,  vol.  61,  p.  363. 

Loeb,  J. :   Dynamik  d.  Lebenserscheinungen,  Leipzig,  1906. 

Loeb,  J.:   Biochem.  Ztschr.,  1911,  vol.  31,  p.  450. 

Metzer  and  Auer:  Am.  Journ.  of  Physiol.,  1908,  vol.  21,  p.  400. 

Nerking:   Munch,  med.  Woch.,  1909,  vol.  29. 

Ransom:   Deut.  med.  Woch.,  1901,  No.  13. 

Schwartz:  Zentralbl.  f.  Physiol.,  vol.  23. 

Wertheimer  et  Lepage:  Compt.  rend,  de  la  Soc.  de  Biol.,  1901,  p.  759. 

IMMUNITY. — Many  forms  of  immunity  are  based  upon  chemical 
distoxication,  this  being  particularly  true  for  immunity  to  toxins 
(see  p.  547),  for,  as  previously  stated  (p.  552),  the  antitoxins,  which 
have  been  formed  in  the  body,  circulate  about  in  the  blood  and  capture, 
as  it  were,  the  toxins  which  may  enter  it. 

Apparently  the  antitoxins  penetrate  only  with  difficulty  or  not  at  all  into 
the  pericellular  lymph-spaces  or  the  cells  themselves,  for,  if  a  toxin  without  enter- 
ing the  circulation  be  brought  in  contact  with  the  susceptible  cells,  it  produces 
its  typical  effects  upon  them  even  in  immunized  animals  whose  blood  is  full  of 
antitoxin  (Meyer,  Hume,  Ransom,  Gley).  Many  other  poorly  diffusing  bodies 
behave  in  a  similar  fashion.  For  example,  sodium  ferrocyanide  solution  may  be 
injected  into  the  blood  without  producing  any  notable  effect,  but,  if  the  spinal 
cord  itself  has  been  injured  by  a  small  puncture,  or  cut  so  that  the  poisoned 
cerebrospinal  fluid  can  penetrate  to  it,  violent  symptoms  of  poisoning  immediately 
appear. 

Immunity  to  toxins  is  consequently  practically  a  humoral  one,  and, 
with  the  exception  of  congenital  insusceptibility,  thus  far  it  has  not 
been  possible  to  demonstrate  or  produce  a  cellular  immunity  *  except 
in  the  case  of  the  immunity  of  the  red  cells  to  eel  serum  (Tschisto- 
witsch). 

On  the  other  hand,  immunity  to  all  other  poisons  is  almost  always 
cellular,  whether  it  be  a  natural  one  or  one  acquired  by  habituation. 

The  immunity  of  the  rabbit  to  atropine  appears  to  form  an  exception  to 
the  rule,  for,  according  to  Fleischmann,  the  serum  of  rabbits  possesses  the  power 
of  destroying  atropine,  a  property  not  possessed  by  the  blood  of  goitrous  rabbits, 
which  are  quite  susceptible  to  atropine  (Cloetta). 

Salamanders  are  very  insusceptible  to  curare,  and  it  has  been  claimed  that 
this  immunity  can  be  transferred  to  other  animals  by  the  injection  of  sala- 
mander blood,  but  Heuser  was  unable  to  confirm  this. 

In  many  cases  we  to  a  certain  extent  understand  the  chemical 
agencies  with  which  the  cells  render  poisons  harmless  or  with  which 
they  defend  themselves.  Thus,  the  liver-cells  neutralize  acids  with 
ammonia,  which  otherwise  would  be  synthetized  into  urea,  and  distoxi- 
cate  numerous  poisons  by  conjugating  them  with  glycuronic  and 
sulphuric  acids  or  by  oxidizing  or  reducing  them.  These  chemical 
powers  of  the  cells  may  be  very  decidedly  augmented  by  exercise; 
for  example,  by  the  administration  of  increasing  doses  it  is  possible 
to  increase  the  power  of  conjugating  camphor  with  glycuronic  acid 
(Schmiedeberg  u.  Meyer)  or  the  power  of  destroying  morphine 

*  Genetically,  immunity  to  toxins  is,  however,  cellular,  for  the  antitoxins 
are  reaction  products  and  cast-off  portions  of  cells. 


574  PHARMACOLOGICAL  REACTION  FACTORS 

(Faust).  By  gradually  storing  up  calcium  and  transforming  the 
soluble  fluoride  into  the  insoluble  calcium  fluoride,  yeast  cells  can 
accustom  themselves  to  a  concentration  of  ammonium  fluoride  which 
at  the  start  would  have  been  very  poisonous  (E /front). 

In  other  cases  this  chemical  cellular  immunity  has  not  yet  been 
completely  explained.  For  example,  in  the  above-mentioned  habitua- 
tion  to  morphine,  the  insusceptibility  of  the  cerebral  cells,  which 
apparently  take  no  part  in  the  destruction  of  the  morphine  (Eubsa- 
men)  and  which  in  spite  of  this  become  very  insusceptible  to  this  drug, 
is  entirely  unexplained,  as  is  also  the  relative  immunity  of  the  mor- 
phinist  to  cocaine  (Chouppe).  Equally  unexplained  is  the  great 
natural  immunity  of  the  hedgehog,  chicken,  and  frog  to  cantharidin, 
and  that  of  the  cardiac  muscle  of  the  toad  to  digitalis-like  substances. 
Surprising  but  still  capable  of  explanation  is  the  immunity  of  certain 
moulds  (Penic.  glaucum,  etc.),  which  can  live  in  solutions  containing 
from  1  to  2  per  cent,  of  CuS04,  while  others  (for  example,  Muc. 
mucedo)  are  killed  by  0.016  per  cent,  of  this  salt,  and  algae  even 
by  1  in  a  billion.  In  this  case  the  immunity  is  due  to  the  impermeabil- 
ity of  the  cell  wall  of  the  Penic.  glaucum  for  this  salt.  [This  mould 
shows  the  same  insusceptibility  to  Zn  and  to  Hg  salts  (Pulst).] 

On  the  other  hand,  it  goes  without  saying  that  toxic  substances 
cannot  produce  their  specific  effects  in  organisms  in  which  the  corre- 
sponding susceptible  organs  are  either  not  at  all  or  not  sufficiently 
developed.  In  animals  which  have  no  vomiting  centre  apomorphine 
cannot  produce  emesis,  and  strychnine  cannot  cause  reflex  convulsions 
in  foetuses  and  new-born  animals,  in  which  the  spinal  cord  is  not  yet 
completely  developed  (Gusserow). 

Moreover,  when  the  later  effects  of  a  toxicological  action,  such  as 
the  secondarily  caused  death,  are  alone  noted  and  used  as  the  criterion 
and  measure  of  immunity,  paradoxical  results  are  obtained.  In  such 
case  frogs  would  appear  very  immune  to  curare,  because  paralysis  of 
the  respiration  does  not  kill  them  so  long  as  their  skin  is  exposed  to 
the  air;  and  mice  would  appear  relatively  immune  to  CO,  for  in  the 
presence  of  a  low  external  temperature  they  are  able  to  withstand 
otherwise  rapidly  fatal  amounts  of  this  gas  because  they  cool  off 
rapidly  to  the  surrounding  temperature  and,  like  hibernating  animals, 
so  lessen  their  metabolism  that  they  are  able  to  get  along  with  the 
small  amount  of  oxygen  which  is  still  brought  to  them  by  the  haemo- 
globin (Bock).  Further,  the  foetus  in  utero  supports  without  direct 
damage  long-continued  morphine  or  chloroform  poisoning,  because  it  . 
does  not  use  its  own  respiratory  organs,  but,  when  it  is  born  and  be- 
comes dependent  on  its  own  respiration,  it  is  extremely  readily  killed 
by  the  smallest  quantities  of  morphine  or  chloroform.  This  is  the 
explanation  of  the  fact  that  a  deep  morphine  or  chloroform  narcosis, 
induced  in  the  mother  a,  short  time  before  or  during  the  birth,  imperils 
the  life  of  the  child,  although  this  is  not  the  case  during  the  pregnancy. 


FACTORS  AFFECTING  DRUG  ACTIONS  575 

BIBLIOGRAPHY 

Bock,  Job.:   Exp.  Unders.  over  kulilte  intox.,  Kopenhagen,  1895. 

Chouppe:   Compt.  rend.  Soc.  Biol.,  1889. 

Cloetta:  Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  63,  p.  427. 

Effront:  cited  from  Ergebn.  d.  Physiol.,  1907,  vol.  6,  p.  71. 

Faust:  Arch  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  44,  p.  217. 

Fleischmann:  Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  62,  p.  518. 

Gley:  Compt.  rend.  Ac.  Sc.,  November,  1904. 

Gusserow:  Arch.  f.  Gyn.,  1871,  vol.  3,  p.  241;  vol.  13,  p.  63. 

Heuser:  Arch,  intern,  de  pharm.,  1902,  vol.  9. 

Meyer  and  Ransom:  Arch.  f.  exp.  Path.  u.  Pharm. 

Pulst:  Ergebn.  d.  Physiol.,  1907,  vol.  6,  p.  75. 

Pulst:   Jahrb.  f.  wissenschaftl.  Botanik,  vol.  37,  p.  205. 

Riibsamen:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908,  vol.  59,  p.  227. 

Schmiedeberg  u.  Meyer:  Ztschr.  f.  physiol.  Chemie,  1879,  vol.  3,  p.  422. 

Tschistowitch:  Ann.  de  1'Inst.  Pasteur,  1899,  vol.  13,  p.  406. 

SYNERGISM. — If  the  weakening  or  prevention  of  the  action  of  one 
drug  by  that  of  another  be  called  antagonism,  the  one-sided  or  recipro- 
cal augmentation  of  such  action  may  be  termed  synergism  (Fuhner) . 
As  this  phase  of  pharmacology  has  thus  far  been  the  subject  of  com- 
paratively few  exact  investigations,  our  knowledge  of  it  is  relatively 
slight. 

An  increased  carbon-dioxide  tension  in  the  blood  (diminution  of 
the  alkaline  carbonates  in  acid  intoxication)  favors  the  toxic  action 
of  the  chlorates  on  the  red  blood-cells,  perhaps  because  of  an  increased 
liberation  of  free  chloric  acid.  Another  example  is  furnished  by  the 
combined  effects  of  cocaine  and  epinephrin,  Frohlich  and  Loewi  hav- 
ing found  that  doses  of  cocaine  which  by  themselves  produce  no  appre- 
ciable effects  very  markedly  increase  the  effects  of  epinephrin  on  the 
blood-vessels,  the  muscles  of  the  bladder,  the  dilator  of  the  iris,  etc. 
In  this  case  the  effects  cannot  be  considered  as  due  to  a  simple  summa- 
tion of  similar  pharmacological  actions,  for  they  are  altogether  too 
great.  At  present  no  satisfactory  explanation  for  the  above  can  be 
given,  and  for  the  present  we  must  satisfy  ourselves  with  merely 
stating  that  the  cocaine  produces  a  sensibilization  comparable  to  the 
sensibilization  of  light-sensitive  substances  or  to  the  action  of  the 
mordants  in  dyeing. 

Of  much  greater  practical  importance  is  the  synergism  of  the 
narcotics, — for  example,  the  combined  effects  of  scopolamine  and  mor- 
phine (see  p.  79),  of  morphine  and  ether  or  nitrous  oxide,  of  scopo- 
lamine and  ure thane,  of  magnesium  sulphate  and  chloroform  (Melt- 
zer,  Biirgi).  A  similar,  or  rather  an  analogous,  phenomenon  is  the 
very  powerful  action  exerted  on  the  heat-regulating  centre  by  combina- 
tions of  certain  convulsant  poisons  and  hypnotics  (see  p.  473). 

Such  augmentation  of  pharmacological  actions  may  be  determined 
quantitatively  with  greater  exactness  with  combinations  of  hsemolytie 
substances.  Mixtures  of  hasmolytic  sera  or  mixtures  of  other  indiffer- 
ent ha?molytie  agents — for  example,  mixtures  of  saponin  and  ammonia 


576  SYNERGISM 

— produce  a  much  greater  amount  of  haemolysis  than  would  correspond 
to  the  effects  of  the  separate  haemolytic  agents  (Cernovodeanu, 
Arrkenius) . 

In  all  these  cases  we  are  dealing  with  the  combined  action  of 
pharmacologically  dissimilar  substances,  for  pharmacologically  sim- 
ilar substances  simply  produce  the  summation  of  their  separate 
actions. 

While  Honigmann's  experiments  with  mixed  narcosis  with  ether  and  chloro- 
form or  ether  and  alcohol  apparently  indicate  a  potentiation,  Biirgi  and  Hadelon 
have  not  been  able  to  confirm  his  results  in  experiments  which  are  free  from 
sources  of  error.  However,  theoretically  such  a  potentiation  could  be  possible, 
for  Fiihner  has  shown  that  the  solubility  of  chloroform  in  water  is  diminished 
by  the  addition  of  ether,  and  consequently  the  distribution  coefficient  of  such  a 
mixture  between  water  and  oil  (see  p.  105)  is  altered  in  such  a  fashion  as  to  favor 
an  augmentation  of  its  narcotic  effects.  However,  this  alteration  is  so  slight 
in  those  solutions  of  the  narcotics  which  actually  are  formed  in  the  body  during 
anaesthesia,  that  they  are  practically  of  no  significance. 

It  consequently  appears  as  if  the  function  of  cells  is  more  markedly 
and  more  readily  influenced  when  a  smaller  number  of  different  con- 
stituents of  their  protoplasm  is  acted  upon  chemically  or  physically 
than  is  the  case  when  a  larger  number  of  similar  constituents  are  thus 
acted  upon. 

Apparently  the  same  holds  true  for  the  action  of  toxic  substances 
on  lower  organisms.  Lepine  has  recommended  for  parenchymatous 
disinfection  a  mixture  of  several  antiseptics  in  such  extreme  dilution 
that  no  harmful  effect  either  on  the  tissues  treated  or  on  the  pathogenic 
bacteria  could  be  expected.  The  mixture  of  these  different  antiseptics, 
however,  proved  to  be  very  efficient  antiseptically,  but  completely 
harmless  for  the  host,  because  the  larger  number  of  the  ingredients 
were  by  themselves  hardly  toxic  at  all.  If  the  dilutions  employed 
by  Lepine  are  noted,  it  is  apparent  that  the  antiseptic  effect  of  the 
whole  mixture  cannot  be  explained  as  the  result  of  simple  addition. 
However,  systematic  investigations  of  such  potentialized  effects  of 
antiseptic  mixture  have  not  yet  been  conducted.* 

More  recently  such  combination  methods  have  been  employed  by 
Ehrlich  in  the  treatment  of  trypanosome  diseases,  he  having  found  that 
the  combination  of  less  active  trypan  dyes  with  other  less  toxic  basic 
dyes  formed  very  effective  mixtures,  and  having  obtained  similar 
results  with  the  proper  combination  of  different  arsenic  compounds. 

It  may  be  that  the  same  principle  lies  at  the  bottom  of  the  favor- 
able therapeutic  effects  which  the  older  medicine  often  endeavored  to 
obtain  by  the  use  of  mixtures  of  different  drugs.  In  this  connection 
mention  may  be  made  of  the  practical  value  of  combinations  of 
cathartics.  The  old  experience  that  opium  is  distinctly  more  efficient 
in  quieting  the  intestine  and  relieving  colic  than  is  accounted  for 

*  The  synergism  of  phenol  and  the  cresols  and  solutions  of  salts  rests  upon 
a  quite  different  basis,  being  explainable  physically  (see  p.  504). 


HYPERSUSCEPTIBILITY  577 

by  the  morphine  contained  in  it,  may  be  explained  as  resulting  from 
the  synergistic  action  of  its  various  alkaloids. 

BIBLIOGRAPHY 

Arrhenius:   Communicat.  de  PInst.  Seroth.  de  1'gtat  danois,  1908,  vol.  2. 
Burgi:  Deut.  med.  Woch.,  1910,  Nos.  1  and  2. 
Cernovodeanu,  Henri:   Compt.  rend.  Soc.  Biol.,  1905. 
Cernovodeanu,  Henri:  Compt.  rend.  Ac.  Sc.,  1905. 
Ehrlich,  Paul:  Berl.  klin.  Woch.,  1907,  Nos.  9-12. 
Frohlich  u.  Loewi:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62. 
Fiihner:  Miinch.  med.  Woch.,  1910,  1911,  p.  179. 
Honigmann:  Arch.  f.  klin.  Chirurgie,  1899,  vol.  58. 
Lgpine:  Rev.  de  m^d.,  1886,  p.   184. 

Madelung:  Arch.  f.  exp.  Path.  u.  Pharm.,  1910,  vol.  62,  p.  409. 
Meltzer:  Berl.  klin.  Woch.,  1906,  No.  3. 
Rotter:   Zbl.  f.  Chir.,  1888. 

HYPERSUSCEPTIBILITY. — While  in  the  preceding  paragraphs  it  has 
been  possible  to  explain  at  least  a  portion  of  the  various  insuscepti- 
bilities as  the  result  of  antagonism, — or,  more  correctly  expressed,  as 
the  result  of  the  fact  that  certain  chemical  substances  combine  with  or 
destroy  each  other, — on  the  other  hand,  it  appears  that  the  explanation 
for  certain  types  of  hypersusceptibility  or  idiosyncrasy  is  to  be  found 
in  the  synergistic  action  of  two  or  more  substances.  Thus,  in  accord- 
ance with  certain  observations  previously  noted,  it  may  be  possible  to 
explain  the  extreme  susceptibility  of  certain  individuals  to  cocaine 
as  due  to  the  fact  that  in  these  individuals  there  is  from  the  start  an 
exaggerated  tone  of  the  sympathetic  system,  which  is  constantly  kept 
in  a  state  of  excitation  by  epinephrin,  so  that  even  the  slightest  aug- 
mentation of  this  tone  produces  exaggerated  effects. 

In  a  similar  fashion  Eppinger  and  Hess  attribute  abnormal  susceptibility 
to  pilocarpine  to  an  abnormally  high  vagus  tone,  which  in  turn  is  attributed  by 
them  to  the  action  of  a  vagotonic  hormone. 

Frohlich  and  Chiari  have  shown  that  the  excitability  of  the  vege- 
tative nervous  system  and  of  the  cerebrospinal  nerve-endings  is  mark- 
edly augmented  by  diminishing  the  lime  content  of  the  body,  sub- 
stances administered  to  an  animal  or  formed  in  its  own  metabolism 
which  deprive  the  body  of  lime — e.g.,  oxalic  acid — rendering  it  abnor- 
mally susceptible  to  drugs  exerting  such  pharmacological  actions.  The 
same  seems  also  to  hold  good  for  many  phlogogenetic  substances,  for, 
according  to  Chiari  and  Januschke,  the  degree  in  which  the  vessels 
become  permeable  and  in  which  transudations  occur  is  dependent  on 
the  lime  content  of  the  tissues,  its  augmentation  hindering  the  forma- 
tion of  transudates  and  osdema  while  its  diminution  increases  these. 
The  reaction  of  the  skin  to  phlogogenetic  stimuli  is  also  dependent  in 
the  same  way  upon  its  lime  content  (see  p.  495). 

Calcium  is,  however,  not  the  only  constituent  of  protoplasm  the 

varying  amount  of  which  determines   or  influences  its  momentary 

power  of  reacting  to  drugs  an<?  poisons,  but  is  only  a  better  known 

and  more  thoroughly  investigated  example  of  the  importance  of  the 

37 


578  FACTORS  AFFECTING  DRUG  ACTIONS 

composition  of  the  tissue  fluids,  and  one  which  renders  it  probable  that 
the  remarkable  susceptibility  of  many  individuals  to  certain  sub- 
stances, such  as  morphine,  strawberries,  shell-fish,  etc.,  is  dependent 
on  a  peculiar  chemical  composition  of  the  tissue  fluids  and  proto- 
plasm.* The  old  name  idiosyncrasy,  meaning  peculiar  mixture,  would 
therefore  appear  based  upon  a  fundamentally  correct  idea. 

The  nature  of  certain  other  kinds  of  hypersusceptibility  is  still 
entirely  inexplicable,  this  being  particularly  the  case  with  acquired 
cellular  hypersusceptibility  to  certain  toxins.  If  an  animal  receive 
small  doses  of  tetanus  toxin,  which  produce  almost  imperceptible  or  no 
toxic  effects,  its  central  nervous  system  becomes  hypersusceptible  to 
this  toxin,  so  that  amounts  thereof  which  ordinarily  would  have  no 
effect  cause  the  development  of  severe  tetanus  (v.  Behring). 

This  hypersusceptibility  of  the  nervous  system  may  be  readily  demonstrated 
by  the  injection  of  tetanus  toxin  into  the  nerve-trunks  or  the  central  nervous 
system  of  immunized  animals,  whose  blood  and  other  body  fluids  contain  tetanus 
antitoxin  ( Meyer  u.  Ransom ) .  It  manifests  itself  even  more  clearly  in  animals 
which  have  been  inoculated  intraneurally  with  a  dose  of  tetanus  large  enough 
to  cause  only  a  slight  local  tetanus.  In  such  animals  no  antitoxin  is  formed,  but, 
on  the  contrary,  after  the  lapse  of  2  or  3  weeks  an  extreme  hypersusceptibility 
develops,  so  that  a  severe  general  tetanus  results  from  the  subcutaneous  injection 
of  amounts  of  the  toxin  which  ordinarily  would  produce  no  tetanus  (Loewi  u. 
Meyer). 

This  might  all  be  looked  upon  as  due  to  the  summation  of  the 
action  of  the  two  doses  were  it  not  for  the  paradoxical  fact  that  two 
or  more  very  small  doses,  injected  into  the  spinal  cord  at  long  intervals, 
produce  much  greater  toxic  effects  than  a  many  times  larger  dose 
injected  at  one  time.  This  might  be  explained  on  the  assumption,  that, 
when  one  large  dose  of  the  toxin  is  administered,  those  tissues  which 
are  not  specifically  susceptible — the  connective  tissues,  etc. — absorb 
the  toxin  relatively  more  rapidly  or  in  larger  amounts,  in  comparison 
with  the  nervous  protoplasm,  than  is  the  case  when  a  small  dose  is 
administered,  in  which  latter  case  the  nerves  would  absorb  relatively 
more  of  the  toxin ;  in  other  words,  on  the  assumption  that  the  distribu- 
tion of  the  toxin  to  the  different  tissues  varies  greatly  with  its  varying 
concentration.  In  a  previous  section  (p.  562)  a  similar  behavior  of 
pharmacological  agents  has  already  been  instanced.  Otherwise  there 
remains  only  the  assumption  that  the  first  subliminal  poisoning  has 
gradually  produced  a  persistent  alteration  of  the  condition  of  the 
spinal  cord,  as  a  result  of  which  its  power  of  reacting  to  this  toxin 
has  been  very  gradually  augmented, — in  other  words,  the  assumption 
of  a  sensibilization,  a  true  cellular  hypersusceptibility. 

A  certain  analogy  for  this  is  furnished  by  the  so-called  autocatalytic  reac- 
tions. Catalyzers  are  substances  which  accelerate  or  facilitate  certain  chemical 

*  In  this  connection  see  Reid  Hunt,  The  Effects  of  a  Restricted  Diet  and  of 
Various  Diets  on  the  Resistance  of  Animals  to  Certain  Poisons,  Hyg.  Labor.  Bull. 
No.  69,  Washington,  June,  1910. 


ANAPHYLAXIS  579 

reactions.  Now,  there  are  certain  chemical  reactions  in  which  a  catalyzer  is 
produced  which  accelerates  this  very  same  reaction,  so  that,  when  it  has  once 
started,  it  progresses  with  steadily  increasing  rapidity  and  intensity,  the  elements 
which  react  with  each  other  being  sensibilized  to  each  other.  Numerous  biochemi- 
cal processes  exhibit  this  progressive  character  (Robertson). 

Behring  and  Kitashima  have  apparently  shown  that  something  of 
the  same  kind  occurs  in  rabbits,  repeatedly  slightly  poisoned  with 
diphtheria  toxin,  in  whom  hardly  any  antitoxin  is  formed. 

BIBLIOGRAPHY 

Behring:  Allgem.  Ther.  d.  Infektionskrankh.,  1899. 
Behring  u.  Kitashima:   Berl.  klin.  Woch.,  1901,  p.  157. 
Chiari  u.  Frohlich:  Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  64,  p.  369. 
Chiari  u.  Januschke:   Arch.  f.  exp.  Path.  u.  Pharm.,  1911,  vol.  65,  p.  120. 
Eppinger  u.  Hess:  Die  Vagotonie,  Berlin,  1910. 
Loewi  u.  Meyer:  Arch.  f.  exp.  Path.  u.  Pharm.,  1908. 
Meyer  u.  Ransom:  Arch.  f.  exp.  Path.  u.  Pharm.,  1903,  vol.  43,  p.  369. 
Robertson,  Br.:  The  Monist,  1910,  p.  368. 

ANAPHYLAXIS. — Another  type  of  hypersusceptibility,  named  by 
Richet  "anaphylaxis"  (ana — without,  phylos — weapon),  appears  to 
be  of  an  entirely  different  nature. 

If  a  foreign  proteid  substance,  either  toxic  or  non-toxic,  be  subcu- 
taneously  or  intravenously  administered  to  an  animal,  after  a  lapse 
of  some  weeks  the  intravenous  injection  of  a  very  small  amount  of  this 
same  substance  (and  this  substance  only)  causes  a  very  rapid,  severe, 
and  often  fatal  poisoning,  which  in  its  character  is  always  the  same  no 
matter  what  kind  of  proteid  has  been  used  to  sensitize  the  animal. 
The  symptoms  produced  vary,  however,  with  the  species  of  animal 
used,  being  in  the  case  of  dogs  those  of  vascular  paralysis,  vomiting, 
purging,  dyspnrea,  general  muscular  weakness,  and  unconsciousness, 
while  in  the  rabbit  they  are  chiefly  due  to  a  peripherally  induced 
spasm  of  the  bronchial  muscles  which  mechanically  prevents  respira- 
tion. Witte's  peptone,  when  injected  intravenously,  produces  the 
same  symptoms  in  these  animals  (Biedl  u.  Kraus),  so  that  it  may  be 
concluded  that  the  anaphylaxis  poison  is  identical  with  or  similar  to 
some  substance  present  in  this  mixture. 

It  would  appear  that,  as  a  result  of  the  first  injection  of  the  anti- 
gen, the  organism  gradually  manufactures  a  specific  antibody  which, 
when  it  again  comes  into  contact  with  the  antigen,  forms  a  substance 
which  is  acted  upon  and  decomposed  by  a  peptic  ferment  present  in 
the  blood-plasma,  with  the  formation  of  the  anaphylactic  poison  which 
causes  the  anaphylactic  shock.  Inasmuch  as,  if  the  animal  survives 
this  shock,  he  is  immune  to  this  antigen,  it  would  seem  that  the  anti- 
body or  the  hypothetical  ferment  in  the  blood  has  been  entirely  con- 
sumed in  the  first  anaphylactie  reaction.  This  antibody  persists  in 
the  blood  for  a  long  time,  sometimes  for  many  years,  and  may  be 
transferred  to  normal  individuals  if  they  be  transfused  with  such  a 


580  FACTORS  AFFECTING  DRUG  ACTIONS 

serum,  so  that  they  also  react  to  the  antigen  in  question  with  an  acute 
anaphylactic  shock.* 

In  man  such  anaphylaxis  has  been  observed  particularly  in  indi- 
viduals treated  with  various  antitoxic  sera,  the  symptoms  consisting  of 
exanthematous  eruptions,  oedema,  fever,  general  malaise,  and  collapse. 
Similar  symptoms  also  occur  in  specifically  susceptible  individuals 
after  eating  certain  foods,  among  others  egg  albumen,  and  in  this 
case,  too,  the  symptoms  are  to  be  attributed  to  an  anaphylactic  pre- 
disposition acquired  in  some  fashion  or  other  (Bruck,  Klausner). 
Thus  far  we  have  been  unable  to  gain  any  further  insight  into  the 
nature  of  these  remarkable  phenomena,  and  still  less  explained  is  the 
hypersusceptibility  of  the  tissues  observed  in  repeated  infection  with 
hay-fever  toxin,  tuberculin,  vaccine,  and  other  bacterial  toxins  (von 
Pirquet).  This  is  also  the  case  with  idiosyncrasies  to  certain  chemical 
well-defined  substances,  among  which  special  mention  should  be  made 
of  iodoform  and  antipyrine,  which  in  predisposed  individuals  regularly 
cause  exanthemata  and  osdema,  with  fever,  dyspnoea,  and  pronounced 
lassitude.  Bruck1 's  experiments  have  shown  that  this  predisposition 
may  be  induced  in  animals  by  the  injection  of  the  blood-serum  of 
predisposed  individuals,  and  consequently  it  too  appears  to  be  of  an 
anaphylactic  nature  (Klausner).  Bruck  explains  it  as  follows:  Under 
the  chemical  influence  of  these  substances  a  heterologous  proteid  is 
formed  in  the  body  which  acts  as  an  antigen,  and  when,  following 
the  renewed  ingestion  of  the  drug,  this  is  again  formed,  it  excites  the 
anaphylactic  attack. 

BIBLIOGRAPHY 

Anderson  and  Frost:  Hyg.  Labor  Bull.,  No.  44,  Washington,  1910. 

Biedl  u.  Kraus:  Wien.  klin.  Woch.,  1909,  No.  1. 

Biedl.  u.  Kraus:  Handb.  d.  Tech.  u.  Method,  d.  Immunitatsforschung,  Jena,  1910. 

Bruck,  C.:  Berl.  klin.  Woch.,  1910,  Nos.  12  and  42. 

Friedberger,  E.:   Ztschr.  f.  Immunitatsforschung  u.  exp.  Ther.,  1909-11,  vols.  3-4. 

Friedberger,  E.:   Berl.  klin.  Woch.,  1910,  No.  50. 

Klausner:  Munch,  med.  Woch.,  1911,  Nos.  3,  27  and  28. 

Pfeiffer:  Problem  d.  Anaphylaxie,  Jena,  1910. 

v.  Pirquet:  Allergie.  Ergebn.  d.  inn.  Med.  u.  Kinderheilk.,  1908,  vol.  1,  p.  420. 

Richet:-Frav.  du  lab.  de  phys.,  1909,  vol.  6. 

Richet:  Journal  mgdical  franc.,  Sept.  15,  1910. 

In  the  discussion  of  various  pharmacological  actions,  reference  has 
repeatedly  been  made  to  the  fact  that  pathological  conditions  produce 
alterations  in  the  functions  and  reactions  of  the  various  organs  and 
thus  provide  altered  conditions  for  pharmacological  actions.  Our 
knowledge  of  pharmacological  actions  under  such  conditions  must  in 
many  cases  be  based  solely  upon  clinical  experience  and  observation, 
for,  with  the  exception  of  certain  experimental  infections,  it  is  but  sel- 
dom possible  in  the  laboratory  experimentally  to  produce  and  analyze 
disturbances  similar  to  those  occurring  in  human  disease.  Wherever 

*  For  literature  see  Anderson  and  Frost,  Biedl.  u.  Kraus,  Pfeiffer,  Fried- 
Merger. 


RATIONALISM  VS.  EMPIRICISM  581 

it  has  been  possible  to  do  this  experimentally,  pharmacologists  have 
been  able  to  amplify  the  fundamental  knowledge  obtained  by  experi- 
ments on  normal  animals  by  that  obtained  in  diseased  ones  and  to 
note  the  differences  in  such  actions  as  observed  under  pathological 
conditions.  This  has  been  especially  the  case  in  the  investigation  of 
the  antipyretics  and  of  those  drugs  influencing  the  circulation,  the 
respiration,  the  formation  of  blood,  the  metabolism,  and  the  processes 
of  inflammation;  Such  experimental  therapy  has  thus  been  able  to 
give  the  explanation  for,  and  the  theoretical  foundation  of,  not  only 
etiotropic  treatment,  but  also  for  the  symptomatic  treatment  of  many 
pathological  conditions. 

However,  in  so  far  as  it-  is  not  a  question  of  purely  etiotropic  phar- 
macological actions,  it  is  always  the  analytical  experiment  on  normal 
animals  or  organs  which  forms  the  actual  foundation  for  our  phar- 
macological knowledge  and  the  deductions  drawn  therefrom.  Conse- 
quently, it  is  entirely  correct  to  question  whether,  and  how  far, 
these  deductions  hold  true  for  pharmacology  in  its  connection  with 
normal,  and  particularly  in  connection  with  diseased,  human  beings. 

Although,  with  the  exception  of  the  cerebrum  and  the  skin,  human 
organs  and  their  reactions  do  not  differ  essentially  from  those  of  other 
mammals,  and  consequently  pharmacological  laws  discovered  by  ex- 
periments on  animals  may  in  principle  be  applied  to  man,  still  there 
are  sufficient,  although  not  always  clearly  understood,  reasons  why  the 
phenomena  observed  in  pharmacological  experiments  on  animals  do 
not  always  agree  entirely  with  the  therapeutic  effects  as  observed  at 
the  bedside.  As  a  matter  of  fact,  it  is  the  outspoken  or  quietly  cher- 
ished opinion  of  many  physicians  that  the  effects  of  drugs  in  human 
patients  can  in  no  way  be  reconciled  with  those  observed  in  animal 
experiments,  and  that  the  latter  are,  generally  speaking,  of  no  value 
for  practical  therapeutics,  in  which  experience  by  the  bedside  should 
be  the  sole  guide  for  the  physician. 

On  the  surface  this  view  appears  to  be  correct,  for  there  is  no 
doubt  that  with  the  aid  of  such  experiences  the  physician  may  be  a 
successful  therapeutist,  just  as  an  experienced  peasant  may  be  a  good 
farmer.  It  would  be  unfortunate  if  neither  the  cultivation  of  the 
ground  nor  the  treatment  of  the  sick  were  possible  without  theoretical 
understanding,  for  this  is  neither  desired  nor  possessed  by  every  one. 
It  is  also  not  to  be  questioned  that  the  practically  experienced  man 
possessing  no  theory  would,  for  the  time  at  least,  be  a  more  useful 
farmer  or  physician  than  the  theoretical  individual  who  possesses  no 
practical  experience.  Advances,  however  (for  example,  in  agricul- 
ture the  employment  of  artificial  fertilizing  agents),  are  only  very 
exceptionally  made  without  the  aid  of  theoretical  knowledge,  and  for 
this  reason  alone,  not  to  speak  of  others,  theoretical  knowledge  is  abso- 
lutely indispensable  for  practical  therapeutics.  Every  apparently 
erroneous  dictum  of  pharmacology  is  probably  capable  of  sooner  or 


582  FACTORS  AFFECTING  DRUG  ACTIONS 

later  being  explained,  and  if  theory  is  to  become  a  guide  for  practice 
it  must  never  disregard  those  practical  experiences  which  rest  on  a 
firm  foundation.  As  a  matter  of  fact,  there  can  be  absolutely  no 
contradiction  between  correct  theory  and  correctly  interpreted  prac- 
tical experience.  Actually  the  often  proclaimed  contradiction  between 
pharmacological  theory  and  clinical  experience,  as  between  theory 
and  practice  in  any  case,  is  due  to  nothing  else  than  the  fact  that, 
from  premises  gained  by  experiments,  incorrect  or  too  far-reaching 
deductions  are  drawn  and  built  up  to  form  an  incorrect  theory.  The 
apparent  discrepancies  between  theory  and  practice  will  always  show 
themselves  wherever  the  adequate  and  necessary  conditions  of  the 
experiment  are  very  numerous  and  only  to  be  learned  and  controlled 
gradually.  This  must  be  the  case  particularly  often  in  medicinal 
therapy,  where  in  most  cases  the  effects  observed  will  not  be  solely 
the  direct  pharmacological  action  of  the  drug,  but  will  be  the  result 
of  many  complicating  factors. 

For  example,  in  the  intestine  the  effect  of  the  pharmacological  action  of 
opium  may  express  itself  in  an  evacuation  of  the  bowels  after  a  constipation 
lasting  for  many  days,  or,  conversely,  by  a  constipation  after  a  diarrhoea  lasting 
an  equal  time  (see  p.  192)  ;  or  in  the  kidneys,  according  to  circumstances,  the 
pharmacological  action  of  pilocarpine  may  result  in  augmentation  or  diminu- 
tion of  the  kidney  secretion  (see  p.  375). 

It  is  consequently  necessarily  futile,  and  therefore  unjustifiable, 
to  demand  that  from  pharmacological  experiments  alone  one  should 
deduce  and  predict  the  successful  action  of  a  drug  in  each  separate 
pathological  condition,  for  this  is  just  as  impossible  as  it  would  be 
to  foresee  the  whole  clinical  symptom  complex,  which  will  result  in 
any  given  case  from  a  certainly  known  cause  of  disease,  such  as  an 
infection  with  typhoid;  for  here,  too,  in  different  cases,  different 
secondary  conditions  result  from  the  primary  disturbance,  which  are 
dependent  on  various  fortuitous  conditions,  just  as  is  the  case  with 
the  symptoms  resulting  from  a  pharmacological  action.  In  order 
to  foresee  with  a  certain  exactness  those  symptoms  on  which  will  de- 
pend the  therapeutic  effects,  it  would  be  necessary  that  one  could 
correctly  judge  of  the  condition  of  all  the  organs  of  the  body  which 
may  be  of  importance  in  a  given  case.  Just  here  it  is  that  the  phy- 
sician's art,  and  his  intuition,  which  has  been  ripened  by  experience, 
should  play  its  part  in  combination  with  his  theoretical  knowledge. 


INDEX 


ABORTIFACIENTS,   223,   224.      (See   also 
Uterine    movements,   drugs   influenc- 
ing) 
ABRIN,  eye  action  in,  160 

phlogogenic  action,  483,  490 
ABSORPTION     from     blood     by     cells 

562 

by  intestine,  173,  174 
by  stomach,  172,  173 
ACCELERATOR,  actions  (see  under  Circu- 
lation) 

ACETANILIDE,  478 

ACETARSANILATE  (see  Arsacetin) 

ACETPHENETIDIN,  478 

ACETYL-SALICYLIC  ACID,  antipyretic  ac- 
tion of,  472 
excretion  and  fate,  472 
therapeutic  actions,  480.    (See 
also  under  Salicylic  Acid  and 
Salicylates) 

ACID,  acetic,  as  counterirritant,  487 
boric,  as  antiseptic,  509 
toxicity  of,  508,  509 
carbolic  (see  Phenol) 
chromic,  as  caustic,  491 
formic,  as  counterirritant,  487 
hydrochloric,   biliary  secretion,   ac- 
tion on,  170 
secretin  secretion,  168 
secretion,  drugs  acting  on,  166, 

167 
stomach  movements,  action  on, 

186 

hydrocyanic,  action  on  blood,  450 
lactic,  as  caustic,  491 
nitric,  as  caustic,  491 
phosphoric,    elimination    by    intes- 
tine, 172 

picric,  astringent  action,  493 
pyrogallic  (see  pyrogallol) 
salicylic  (see  Salicylic  acid) 
sulphurous,  as  disinfectant,  506 
tannic  (see  Tannin) 
trichloracetic,  as  caustic,  491 
ACIDOSIS,  421 

central  nervous  system,  effects  on, 

394 

ACIDS,  antagonism  to  alkalies,  569 
autolysis,  action  on,  393 
blood  reaction,  action  on,  393 
caustic  action,  491 
disinfectant  power,  503 
factors  influencing  disinfectant  pow- 
der, 503 

gastric  secretion,  action  of,  on,  165 
local  actions,  394,  491 
metabolism,  action  on,  393-395 
mineral,  as  disinfectants,  506 


ACIDS,  vegetable,  action  on  blood,  449 
ACONITE,  109 

antipyretic  action  of,  466 
local  action,  109 
toxic  action,  110 
ACONITINE  (see  Aconite) 
ACTOL,  513 

ADEQUATE  QUANTITIES,  561 
ADONIDIN,  302 

ADRENALINE  (see  Epinephrin) 
AGARICIN,  antisudorific  action,  376 
AGARICUS  MUSCARIUS,  248 
AGGLUTININS,  549,  560 
AIROL,  520 
ALCOHOL,  43  ff .    (See  also  Alcohol  Group 

and  Alcohol,  ethyl) 
in  acidosis,  50,  433 
amyl,  elimination  in  bile,  170 
in  angina  pectoris,  326 
antidote  to  phenol,  516 
antiseptic  action,  47,  507,  508 
circulation,  action,  48,  258,  274,  316, 

o^4 
circulatory  failure,  in  treatment  of, 

316,  324 

as  counterirritant,  486 
depressing  action  on  nervous  system, 

48 

in  diabetes,  433 
diaphoretic  action  of,  371 
ethyl,  cause  of  toxic  amblyopia, 

144 

euphoric  action,  47 
fate  in  body,  49 
fats,  as  sparer  of,  432 
as  food,  431-433 
for  muscles,  430 
value,  50 

gastric  secretion,  action  on,  167 
habituation  to,  46 
heart,  action  on,  258,  259 
infections,  influence  on,  49 
intracranial  pressure,  action  on,  48 
kidney,  action  on,  359 
methyl,  muscle  function,  action  on, 

430 

toxic  amblyopia,  from,  144 
motor  function,  action  on,  45 
muscle  function,  action  on,  429-431 
perception,  action  on,  47 
proteid,  as  sparer  of,  432 
respiration,  action  on,  46,  47,  334, 

335,  337 

"stimulating"  action,  46 
stomach  absorption,  effect  on,  173, 

346 

temperature  regulation,  action  on, 
49,  455,  473 

583 


584 


INDEX 


ALCOHOL,    vasoconstriction,    action    on, 

326 

vessels,  action  on,  48,  274 
ALCOHOL  GROUP,  43  ff. 

antipyretic  action  of,  473 
diuretic  action,  359 
haemolytic  action,  452 
respiratory  sedative  action  of, 

337 
ALKALIES,  antagonism  to  acids,  569 

blood-reaction,  action  on,  391,  392 
bronchial  mucous  secretion,  action 

on,  343 
in  diabetes,  action  sugar  excretion, 

418 

disinfectant  power  of,  503 
excretion  of,  390 

gastric  secretion,  action  of,  on,  165 
gout,  action  in,  390,  391 
intestinal  glands,  action  on,  172 
local  actions,  392 
metabolism,  action  on,  389-392 
renal  stone,  action  on,  390 
respiratory  centre,  action  on,  333 
skin,  action  on,  487 
stomach,  action  in,  165,  393 
uric  acid,  action  on,  390,  391,  421 
urine,  action  on,  368,  391 
urolytic  action  of,  391 
ALKALOIDS  eliminated  by  intestine,  172 
general  characteristics  of,  22 
narcotic,  mode  of  action,  108 
ALLERGY,  546 
ALOES,  208 

abortifacient  action  of,  208,  223 
bile  secretion,  action  on,  208 
ALOIN,  kidney,  action  on,  208.   (See  also 

Aloes) 

ALTITUDE,  high,  action  on  blood,  444  ff . 
metabolism,  influence  on,  404,  405 
ALUM,  astringent  action  of,  216 
ALUMINUM  ACETATE,  antiseptic  action,  514 

salts  in  inflammation,  495 
ALTPIN,  133,  134 
AMANITA  MUSCARIA,  248 
AMBLYOPIA,  toxic,  due  to  various  drugs, 

144 

AMMONIA,  anaesthetic  action,  120 
as  counter-irritant,  487 
local  action,  487 
respiration,  action  on,  336 
AMMONIUM  BASES,  chemistry  and  phar- 
macology of,  8 
salts,  diaphoretic  action,  372 

expectorant  action  of,  343 
AYML  CHLORIDE,  278 
AYML  NITRITE  (see  also  Nitrites) 
in  angina  pectpris,  327 
coronary  arteries,  action  on,  289 
heart,  action  on,  277 
toxic  effects,  278 
vasodilator  action,  central,  276, 

278 
peripheral,  277,  288 


AMYLENE  CHLORAL,  93 

hydrate,  94 

ANAPHYLACTIC  FEVER,  462 
ANAPHYLAXIS,  579 
from  drugs,  580 
from  food,  580 
from  sera,  579 
from  toxins,  580 
ANAESTHESIA,  circular,  129 
general,  50-83 

accidents  in,  58,  68 
apparatus  for,  75 
clinical  picture,  56 
combined,  78 

synergism  in,   78,   79,  82, 

576 

deglution,  effect  on,  176 
reflexes  during,  59.  (See  also  an- 
aesthetics) 

infiltration,  120,  128 
local,  117-135 
by  cold,  118 
by  compression,  118 
by  local  anaemia,  118 
morphine-scopolamine,  79 
nitrous  oxide,  73 
regional,  123-129 
terminal,  117 
AN^ESTHESIN,  132,  134 

antiphlogistic  action,  493 
ANAESTHETIC  METHODS,  75  ff . 
ANAESTHETIC  A  DOLOROSA,  120 
ANAESTHETICS,  general,  50  ff . 

absorption  and  distribution  of, 

68  ff .,  75 

circulation,  action  on,  63,  68 
haemolytic  action  of,  452 
history  of,  51 
mortality  from,  76 
motor  function,  action  on,  57 
nerve     trunks     in     periphery, 

action  on,  58 
reflex  effects,  60  ff . 
respiration,  action  on,  59  ff. 
sensory  functions,  action  on,  57 
inhalation,  50 
local,  117  ff. 

antiphlogistic  action  of,  482 
ANGINA  PECTORIS,  327  ff.,  330 
ANILINE,  antipyretic  action  of,  462,  473 
blood  action  on,  451 
constitution,  478 
derivatives,  478 

ANISOTONIC  SOLUTIONS,  local  effect,  120 
ANTAGONISM,  568  ff . 

absolute  reciprocal,  571 

by  distoxication,  569 

between  alcohol  group  and  caffeine, 

strychnine,  and  cocaine,  572 
between  atropine  and  chloral,  336 
and  choline,  248 
and  muscarine,  249,  569,  572 
and  physostigmine,  152,  572 
and  pilocarpine,  373,  572 


INDEX 


585 


ANTAGONISM  between  calcium  and  mag- 
nesium, 110,  571 
calcium  and  muscarine,  249 
choline   and   epinephrin,    164,    188, 

189,  568 
curare  and  physostigmine,  9,  152, 

572 
epinephrin  and  calcium,  463 

and  choline,  164,  188,  189,  568 
and  pancreas,  171,  419,  568 
KC1  and  NH4C1,  570 
magnesium  and  calcium,  110,  571 
morphine  and  atropine,  34,  36,  336, 

572 

Na  and  K  ions,  570 
O2  and  CO,  570 
quinine  and  curarin,  570 
various  salts  and  metals,  570 
true,  569 

ANTAGONISTIC  INNERVATION,  567 
ANTHELMINTICS,  521-524 
ANTHRAQUINONE  DERIVATIVES,  207 
ANTHRASOL,  in  skin  diseases,  518 
ANTIARIN,  302 
ANTIBODIES,  549 
ANTI-EMETICS,  178 
ANTIFEBRIN  (see  Acetanilide) 
ANTIFERMENTS,  547 
ANTIGENS,  549 
ANTIMONIAL  compounds  in  trypanoso- 

miasis,  536 

ANTIMONY,  capillary  dilator  action,  289 
as  caustic,  492 
circulation,  action  on,  415 
elimination  by  intestine,  172 
metabolism,  action  on,  414 
and  potassium  tartrate,  emetic  ac- 
tion of,  183  ^ 

expectorant  action  of,  184,  344 
systemic  actions  of,  184 
toxic  actions  of,  183 
ANTIPHLOGISTIC  AGENTS,  481 
analgesic,  492,  493  _ 

ANTIPYRETICS,  analgesic  actions  of,  475 
blood,  action  on,  451 
centrally  acting,  468  ff. 
cerebral  arteries,  action  on,  475 
diaphoretic  action,  374 
in  fever,  464  ff . 

from  puncture,  463, 464 
in  headaches,  475 
hypnotic  actions,  475 
respiration,  action  on,  333 
as    sedatives    to    heat    regulating 

centres,  464—466 
therapeutic  uses  of,  473  ff . 
vessels,  action  on,  276 
ANTIPYRINE  in  fever  from  puncture,  464 
idiosyncrasy  to,  580 
group,  477  ff . 

antipyretic  effects,  468  ff . 
blood-pressure,  action  on,  469 
brain,  action  on  vessels  of,  326 
metabolism,  action  on,  468,  469 


ANTIPYRINE  group,  vasodilating  action 

of,  326,  468,  469 
ANTISEPTICS,  497-520 

aromatic,  514-518 

bile,  action  on,  170 

eye,  action  on,  160 

general,  bacterial  factors  affecting 

resistance  to,  498-500 
mode  of  action,  498-503 
spores,  action  on,  499,  500 
influence   of   dissociability   of, 

501-504 

of  lipoid  solubility,  500, 501 
of  neutral  salts  on,  503,  504 
of  surrounding  media  on, 
504,  505 

in  intestine,  201,  204,  520 

methods  of  investigating,  497,  498 

urinary,  367,  368 
ANTISUDORIFICS,  375,  376 
ANTITOXIC  SERA,  551 
ANTITOXINS,  543  ff . 

formation  of,  549 

limitations  of,  552 

in  milk,  552 

nature  and  properties,  547,  548 

specificity  of,  548 
ANURIA,  reflex,  358 

influence  of  narcotics  on,  359 
APENTA  WATER,  197 
APHRODISIACS,  219 

APO-ATROPINE,     as     contamination     of 
scopolamine,  29 

test  for,  29 
APOMORPHINE,  emetic  action  of,  179 

expectorant  action,  343 

muscles,  action  on,  427 

respiration,  action  on,  335 

systemic  actions,  180 
ARBUTIN,  367 
ARECA  NUT,  523 
ARECOLIN,  anthelmintic  action,  523 

miotic  and  mydriatic  action  of,  153 

sweat  glands,  action  on,  372 
ARGENTAMINE,  514 
ARGENTI  NITRAS  (see  Silver  nitrate) 
ARGONIN,  514 
ARGYRIA,  217,  514 
ARISTOCHIN,  476 
ARISTOL,  520 
ARNICA,  487 

AROMATIC  substances,  fate  in  body,  514 
ARSACETIN,  535,  536 
ARSENIC,  bacteria,  action  on,  411 

blood,  action  on,  410,  433 

bone,  action  on,  410 

capillary  dilator  action,  289,  411 

as  caustic,  492 

central  nervous  system,  toxic  action 
on,  412 

circulation,  action  on,  411 

eaters,  409,  414 

elimination  by  intestine,  172 

excretion  and  fate  in  body,  413 


586 


INDEX 


ARSENIC  group,  404  ff. 

infusoria,  action  on,  410 

intestine,  toxic  action  on,  411,  412 

local  uses,  413 

and  mercury  in  syphilis,  538-539 

metabolism,  action  on,  408  ff. 

mode  of  action  of,  409 

muscular  paralysis  from,  427 

neuritis  from,  412 

organic    compounds,    in    protozoal 

diseases,  531  ff. 
specific  effects  of,  409 
pathological  tissues,  action  on,  411 
plants,  action  on,  409,  411 
poisoning,  acute,  411 

chronic,  412 

presence  in  living  cells,  409 
in  syphilis,  536 
therapeutic  actions,  412,  413 
tolerance  to,  409,  413,  414 
toxicology,  410-412 
in  trypanosomiasis,  531  ff. 
yeasts,  action  on,  409,  411 
ARSENIURETTED   HYDROGEN,   hsemolytic 

action  of,  409,  452 
ARSENOPHENYLGLYCIN,  536 
ARSONIUM  BASES,  8 
ASPIDII,  oleoresina,  521,  522 

active  principles  of,  522 
toxicology,  522 

ASPIDOSAMINE,  emetic  action,  180 
ASPIDOSPERMINE,  respiration,    stimulant 

action  on,  335 

ASPIRIN  (see  Acetyl-salicylic  acid) 
ASTHMA,  bronchial,  treatment  of,  345 

iodine  in  treatment  of,  347,  398 
cigarettes,  etc.,  345,  346 
ASTRINGENTS,  alimentary  canal,  action 

in,  212. 

antiphlogistic  actions  of,  493-495 
as  antisudorifics,  376 
caustic  action  of,  213 
eye,  action  in,  160 
obstipating  action  of,  212 
vessels,  action  on,  213 
ATOPHAN,  purine  metabolism,  action  on, 

421 

uric  acid  excretion,  effects  on,  368 
ATOXYL,  534  ff. 

constitution,  535 
derivatives,  534-536 
difference  from  inorganic  arsenic,  409 
optic  neuritis  from,  534 
in  syphilis,  537 
in  toxicology,  534 
in  trypanosomiasis,  534 
ATROPINE,  antagonism  to  chloral,  336 

to  morphine  on  respiration,  34, 

36,  336,  572 
to  muscarine  in  heart.  249,  250, 

569,  571 

to  physostigmine,  152,  572 
to  pilocarpine  in  sweat  glands, 
373,  572 


ATROPINE,  asthma,  action  in,  345 

Auerbach's  plexus,  action  on,  190 
autonomic  nervous    system,    action 

on,  142 

biliary  secretion,  action  on,  169 
and  carbohydrate  tolerance,  418 
central  nervous  system,  action  on,  27 
in  chloroform  death,  68 
circulation,  action  on,  250 
in  collapse,  25 
in  constipation,  192 
constitution,  154 
convulsant  action  of,  24 
deglutition,  effect  on,  176 
in  diabetes,  418 
in  emesis  due  to  morphine,  33 

to  pyloric  spasm,  185 
eye,  action  of  on,  153  ff 
gastric  secretion,  action  of,  on,  166 
heart,  action  on,  249  ff . 
hyperchloridia  action  in,  167 
icterus,  action  in,  253 
idiosyncrasy  to,  156 
immunity  of  rabbit  to,  573 
intestinal  motor  function,  action  on, 

190,  191,  192 

intraocular  tension,  action  on,  155 
lead  colic,  in,  192 
metabolism,  action  on,  382 
in  morphine  poisoning,  36 
mydriatic  action  of,  154  ff. 
occurrence,  153 
ophthalmology,  uses  in,  155 
pancreatic  secretion,  action  of,  on, 

168,  568 
poisoning,  acute,  156 

acute,  treatment  of,  156 
chronic,  156 
pyrqgenic  action  of,  462 
respiration,   stimulating  action  on, 

335,  336 

salivary  secretion,  164 
secretions,  action  on,  155 
stomach  movements,  action  on,  166, 

188 

secretion,  action  on,  166 
substitutes  for,  157 
systemic  actions,  155 
sweat  secretion,  action  on,  375 
therapeutic  uses,  156 
uterine  contractions,  action  on,  222 
atropine-methylium  bromide,  418 
AUERBACH'S  PLEXUS,  action  of  drugs  on, 
190  ff. 

AURICULO- VENTRICULAR      TRACT,      digi- 

talis's  action  on,  266-267 
AUTOLYSIS,    thyroid    substances,    influ- 
ence on,  395 

AUTONOMIC  DRUGS,  intestinal  motor  func- 
tion, action  on,  190 
stomach  movements,  action  on, 

187 

uterine  movements,  action  on, 
222 


INDEX 


587 


AUTONOMIC  nervous  system,  anatomy  and 

physiology  of,  136-138 
antagonism     between     sympa- 
thetic nervous  system  and, 
140 

atropine,  action  of,  on,  142 
choline,  action  of,  on,  142 
muscarine,  action  of,  on,  142 
physostigmine,    action   of,    on, 
142 

BACTERICIDAL  SERA,  558 

BACTERIOLYSINS,  550,  558 

BALSAM  OF  PERU,  518 

BARIUM,  intestinal  motor  function,  action 

on,  191 

poisoning,  sulphates  in,  201 
BATHS,  cold,  antipyretic  action  of,  467 
carbon  dioxide,  486 
salt,  488 
sea,  488 

BELLADONNA  (see  Atropine) 
BENZOATES,  biliary  secretion,  action  on, 

170 

BENZOL,  leucocytes,  action  on,  447 
BETA-EUCAINE  (see  Eucaine  B) 
BETA-IMIDAZOLYLETHYLAMINE,  226,  228 
BETAINE  in  ergot,  225 
BETA-NAPHTHOL  as  intestinal  antiseptic, 

521 

in  skin  diseases,  518 
BETEL  NUT,  523 
BILE  ACIDS,  heart,  depressant  action  on, 

253 

elimination  by,  170 
salts,  biliary  secretion,  action  on,  170 
secretion  of,  antiseptics,  action  on, 

170 

atropine,  action  on,  169 
benzoates,  action  on,  170 
bile  salts,  action  on,  170 
calomel,  action  on,  170 
cathartics,  action  on,  170 
hydrochloric   acid,    action  on, 

170 

oleates,  action  on,  170 
pilocarpine,  action  on,  169 
salicylates,  action  on,  170 
saline  cathartics,  action  on,  170 
soda,  action  on,  170 
BISMUTH  elimination  by  intestine,  172 
gastric  secretion,  action  of,  on,  167 
poisoning,  494 
salts,  in  inflammation,  494 
subgallate,  216 
subnitrate,  absorption  of,  215 

mucous  membranes,  action  on, 

215 

nitrite  poisoning  from,  216 
subsalicylate,  216 
BITTERS,  leucocytes,  action  on,  447 

stomach  absorption,  effect  on,   173 

movements,  effect  on,  187 
BLOOD,  alkalinity  of,  389,  391,  392,  449 


BLOOD,  coagulability  of,  substances  affect- 
ing, 447 

concentration  of,  agents  influencing, 
436 

condensation  of,  435 

pharmacology  of,  435-452 

plasma,    chemical    composition    of, 
drugs  altering,  449 

poisons,  449-452 

pressure  (see  under  Circulation) 

reaction  of,  389,  391,  392 

toxicology  of,  449-452 

viscosity  of,  drugs  affecting,  448 
BORAX,  as  antiseptic,  509 

as  preservative,  509 

BORNYVAL,  115 

BREAD,  gastric  secretion,  action  of,  on, 

165 

BROMDIETHYLACETAMIDE  (see  Neuronal) 
BROMEIGON,  115 

BROMIDES,  central  nervous  system,  ac- 
tion on,  111 

epilepsy,  action  in,  112 

excretion  in  saliva,  165 
in  urine,  113 

metabolism,  action  on,  387 

organic,  115 

retention  in  body,  112 
BROMIPIN,  115 
BROMISM,  114 
BROMOCOLL,  115 
BROMURAL,  97 

BRONCHIAL  SPASM,  drugs  relieving,  345  ff . 
BRUCINE,  action  of,  21 

source  of,  12 

CACODYLIC  ACID,  533 

difference  from  inorganic  arse- 
nic, 409 
CAFFEINE  (see  also  Caffeine  group) 

accelerator,  peripheral,  action    on, 

252 

antagonism  to  narcotics,  25 
beverages,  25,  314 
cerebrum,  action  on,  26 

actions  on  vessels  of,  289,  330 
circulatory  action,  313  ff.,  360,  361 
in  collapse,  25 
constitution,  360 
coronary   vessels,    action   on,    289, 

313,  330 
derivatives,    muscle    and    kidney, 

action  on,  364 

and  digitalis,  compared,  267 
diuretic  action,  360  ff . 
extra-systoles,  power  of  causing,  268 
fate  in  body,  315 
fatigue,  action  in,  429 
general  actions,  363 
glycosuria  from,  419 
heart  action  on,  267,  268 
intracranial  vessels,  action  on,  330 
kidney,  effect  on  blood  flow  through, 

362 


588 


INDEX 


CAFFEINE,  kidney,  excretion  by,  362 

harmlessness  to,  364 
metabolism,  effect  on,  379 
morphine  poisoning,  action  in,  36 
muscle,  action  on,  428 
occurrence  of,  314 
pulse-rate,  effect  on,  268 
respiration,  action  on,  335,  347 
-sodium  benzoate,  subcutaneous  use 

of,  313 
salicylate,  subcutaneous  use  of, 

313 

temperature,  action  on,  314,  462 
toxicology,  26,  314 
in  treatment  of  vascular  depression, 

312  ff. 
vasoconstrictor  centres,  action  on, 

274 
vessels,  action  on,  274,  330 

dilator  action  on,  cerebral,  cor- 
onary and  renal,  289 
renal,  action  on,  330,  362 
group  (see  also  Caffeine) 
constitution,  360 
diuretic  action,  360  ff . 
vasoconstriction,  in   treatment 

of,  330,  331 
CALCIUM,  antagonism  in  heart  between 

muscarine  and,  249 
between  magnesium  and,  110, 

571 

antiphlogistic  action,  495,  496 
elimination  by  intestine,  172 
and  epinephrin,  antagonistic  effects 

on  fever,  463 

ions,  action  on  muscles,  422 
precipitants,  action  on  muscles,  422 

cathartic  action,  198 
toxic  action  of,  496 
vegetative  system  and,  577 
chloride,  remote  astringent  effects, 

495 
hydroxide,  alimentary  canal,  action 

in,  217 

salts,  astringent  effects,  217,  495 
in  inflammation,  495 
leucocytes,  action  on,  447 
sulphide,  depilating  action,  210 
CALOMEL,  absorption  of,  203 

biliary  secretion,  action  on,  170,  204 

cathartic  action,  203 

diuretic  action  of,  204,  356 

as  intestinal  antiseptic,  201,  204,  521 

iodides,  poisonous  interaction  with, 

204 

kidney  action  on,  204 
in  syphilis,  541,  542 
toxic  action,  204 
CAMPHOR,  cardiac  failure,  in  treatment 

of,  310,  316 
central  nervous  system,  action  on, 

24,26 

convulsant  action,  24 
in  collapse,  25 


CAMPHOR,  "curare"  action  in  frog,  8 

as  counterirritant,  diuretic,  action, 

372,  488' 

excretion  and  fate  in  body,  310,  420 
fibrillation,  action  in,  256,  257,  316 
heart,  action  on,  255-257,  310,  316 
in  chloralized,  255,  256 
in  muscarinized,  255 
in  morphine  poisoning,  36 
respiratory  centre,  action  on,  335 
reviving  action  of,  25 
sweat  secretion,  action  on,  372 
systemic  actions,  310 
temperature,  action  on,  473 
therapeutic  uses,  310,  316 
vascular  depression,  in  treatment  of, 

315 
vasoconstrictor  centres,  action  on, 

274 
CAMPHORIC  ACID,  antisudorific  action  of, 

376 

a  respiratory  sedative,  340 
CANNABIS  INDICA,  41 
CANTHARIDIN,  489,  490 

aphrodisiac  action,  219 
immunity  to,  483 
kidney  action  on,  359,  490 
poisoning,  490 

alkalies  in,  490 

therapeutic  employment  of,  490 
CARBOLIC  ACID  (see  Phenol) 
CARBON  DIOXIDE  baths,  486 

central  nervous  system,  action 

on,  394 

narcotic  action,  cause  of,  108 
respiration,  action  on,  332,  333, 

337 

retina,  action  on,  144 
r61e  in  physiology  of  cells,  395 
stomach  absorption,  effect  on, 

173 
stomach  movements,  effect  on, 

186 

viscosity  of  blood,  effect  on,  449 
disulphide,  causing  toxic  amblyopia, 

144 

monoxide,  antagonism  to  Oz,  571 
blood  action  on,  450 
glycosuria,  419 
poisoning,  450,  571 
CARBONIC  ACID  (see  Carbon  dioxide) 
CARDOL,  490 
CARLSBAD  SALTS,  202 
CARMINATIVES,  210 
CARNIFERRIN,  442 
CASCARA  SAGRADA,  208 
CASSIA  ANGTJSTIFOLIA,  207 
CASTOR  OIL  (see  Olium  ricini) 
CATHARTICS,  193-210 

biliary  secretion,  action  on,  170 

classification  of,  196 

diuretic  action  of,  358 

drastic,  eliminated  by  intestine,  172 

large  intestine,  acting  on,  207  ff . 


INDEX 


589 


CATHARTICS,  mode  of  action  of,  195 
saline,  196-203 

alkali  loss  resulting  from,  200 
absorption,  action  on,  196 
antiseptic  (intestinal)  effect  of, 

200 

biliary  secretion,  action  on,  170 
blood,  effect  on,  199 
calcium  precipitation  by,  198 
concentration,  influence  of,  198 
food,  effect  on  utilization  of,  200 
liver,  effects  on,  201 
metabolism,  action  on,  388 
systemic  actions,  197 
small  intestine,  acting  on,  205  ff. 
CAUSTIC  ALKALIES,  local  actions,  491 
CAUSTICS,  491  ff. 
CENTRAL  DEPRESSANTS,  110 

nervous  system,   pharmacology  of, 

11-116 

CEREBRAL  DEPRESSANTS,  27  ff. 
stimulants,  24 

therapeutic  indications  for,  25 
CHAMOMILE,  carminative  action,  210 
CHARCOAL,  alimentary  canal,  action  in, 

212 

poisons,  power  of  absorbing,  212 
CHEMICAL  constitution  and    pharmaco- 
logical action,  relation  between,  98  ff. 
CHLORALAMIDE,  934 
CHLORAL  HYDRATE,  88-92 
acute  poisoning,  91 
antagonism  to  atropine,  336 
as  anti-emetic,  185,  186 
antipyretic  action,  473 
asthma,  action  in,  345 
chronic  poisoning,  92 
circulation,  action  on,  90,  253, 

254,  276 
fate  in  body,  89 
general  action,  88 
habituation  to,  91 
harmful  actions,  90 
heart,  depressant  action  on,  90, 

253-254,  309 
idiosyncrasies  to,  90 
local  action,  88 
pupil,  action  on,  136 
respiration,  action  on,  91,  336, 

338 

therapeutic  employment,  90 
toxicology,  91 
vessels,  action  on;  90,  276 
cerebral,  action  on,  325 
cutaneous,  action  on,  325, 

326 

CHLORATES,  blood,  action  on,  451 
disinfectant   action,  511,  512 
poisoning  by;  512 
CHLORINE,  as  disinfectant,  505,  506 

local  irritant  action  of,  506 
CHLOROFORM,  55  ff . 

anaesthesia,  after  effects,  74 
asthma,  action  in,  345 


CHLOROFORM,  blood  cells,  action  on,  56 
blood-pressure,  action  on,  62 
cardiac  death  from,  64-66 
a  cardiac  poison,  63 
chemistry,  55 

circulation,  action  on,  60  ff . 
concentration  in  air  inspired,  70,  72, 

73 

in  blood,  69,  71 
toxic  to  heart,  63,  64 
as  counterirritant,  486 
death  from,  63-67 

analysis  of  causes  of,  66 
in  man,  66-68 

distribution  in  anesthesia,  103 
excretion  and  fate  in  body,  55 
general  action,  55 
heart,  action  on,  62,  63 

depressant  action  on,  253 
kidneys,  action  on,  74 
local  action,  55 
percentage  in  blood,  69 
respiration,  action  on,  59 
retina,  action  on,  144 
synergism  with  ether,  etc.,  78,  575, 

576 

with  magnesium  sulphate,  575 
temperature,  with  ether,  473 
toxic  action,  56 
late,  74 

vasodilating  action,  central,  62 
vasodilator  action,  peripheral,  288 
vasomotor  centres,  action  on,  60,  61, 

62 

vessels,  action  on,  276 
CHOLAGOGUES,  170 
CHOLESTERIN,  distoxication   of   saponin 

and  crotalus  toxin,  569 
CHOLINE,  antagonism  to  atropine,  248 
to   epinephrin,    164,   188,  189, 

568 
autonomic  nervous  system,  action 

on,  142 
in  ergot,  225 

gastric  secretion,  action  of,  on,  166 
heart,  action  on,  248 
miotic  action  of,  153 
motor  nerve  endings,  action  on,  9 
occurrence,  248 
pancreatic  secretion,  action  of,  on, 

168 

reproductive  organs,  action  on,  218 
salivary  secretion,  action  on,  164 
stomach  movements,  action  of,  on, 

187 

CHOREA,  arsenic  in,  412 
CHRYSAROBIN,  518 
CHRYSOTOXIN,  226 

CICUTOXIN,  action   on  vagus  and  vaso- 
motor centres,  245 
CILIARY  MUSCLE,  pharmacology  of,  145- 

159 

CINCHONA  (see  Quinine) 
CINCHONISM,  477 


590 


INDEX 


CIBCULATION,  231-331 

accelerator  centres,  drugs  acting  on, 

245,  246 
nerves,  peripheral,  drugs  acting 

on,  252 

activity,  effect  on,  231 
blood-pressure  determination,   clin- 
ical, 236,  237 

capillaries,  drugs  acting  on,  288 
capillary  dilators,  288,  289 
cardiac    and    vascular    depression, 

treatment  of,  307  ff. 
compensating  mechanism  of,  231  ff. 
extra-systoles,  267,  268 
factors  controlling,  231-234 
failure,  treatment  of,  307  ff. 
heart,  automatism  of,  244,  253 
bathmotropic  function,  244 
calcium's  importance  for,  269 
accelerator  centres  and  endings, 
influence  of  drugs  acting  on, 
245,  246,  252 

chronotropic  function,  244 
depressants  of,  252-254 
disturbances    of    function    of, 

290 

dromotropic  function,  244 
fibrillation  of,  256,  257 
inhibitory  nerves,  drugs  acting 

on,  248  ff. 

inotropic  function,  244 
motor    centres,    identity    with 

accelerator  endings,  252 
nerves,  drugs  acting  on,  245  ff. 
nutrient  solutions  for,  269,  270 
pharmacology,  244  ff. 
physiology  of,  244, 245 
rate,  influence  of  drugs  affecting 

blood-pressure,  245 
rate,  inhibitory  centre  and  end- 
ings, influence  of  drugs  acting 
on,  245,  246 

stimulating,  drugs,  255  ff. 
vagus  depressants,   peripheral, 

246  ff. 
vagus  centres,  drugs  acting  on, 

245 
methods  of   investigation  of,  234- 

243 
of  cardiac  actions  of  drugs,  238- 

241 

frog's  heart,  239 
isolated  mammalian  heart 
(Hering  -  Bock),      240; 
(Langendorff),  241 
methods  of  investigation  of,  clinical, 

23^237 

experimental,  237,  238 
of  vasomotor  actions,  241-243 
on  excised  arteries,  241, 242 
by  perfusion,  241,  242 
by  plethysmogram,  242,  243 
by  venous  outflow,  242 
pharmacology  of,  231-331 


CIRCULATION,  portal,  reciprocal  balance 

between  systemic  and,  232 
premature  contractions  (see  Extra- 
systoles) 
pulmonary  vessels,  digitalis's  effect 

on  blood-pressure  in,  266 
reciprocal  action  between  heart  and 

vessels,  233 

splanchnic  nerve,  importance  of,  272 
toxines,  action  on,  309 
vascular  crises,  treatment  of,  323 
depression,  treatment  of,  311 
poisons,  483 
vaso-constriction,  treatment  of, 

323  ff. 
vasoconstrictor  (see  also  Vessels  and 

Vasomotor) 

drugs,  central,  273-276 
peripheral,  278-288 
central,  276 

vasodilator  drugs,  peripheral,  288 
vasodilatation,  renal,  hydraemia  as 

cause  of,  359 
substances    causing,     358, 

359 

vasomotor  effects  of  local  applica- 
tions, 289,  290 
vessels,  coronary,  amyl  nitrite,  289 

caffeine,  289,  313,  330 
renal,    drugs    acting    on,    358, 

359 

digitalis,  action  on,  365 
intracranial,  action  of  caffeine 

on,  330 

pharmacology  of,  270-290 
as   a   whole,    effects   produced    by 

drugs  acting  on,  290  ff. 
CITRATES,  cathartic  action  of,  203 

coagulability  of  blood,   action  on, 

448 

CLIMATE,  metabolism,  effect  on,  379 
COAL  GAS  (see  Carbon  monoxide) 
COCAINE,  accelerators,  peripheral,  action 

on,  252 

anaesthesia  of  eye  by,  128 
antagonism  to  chloral,  25 
central  nervous  system,  action  on, 

26,  125 
cerebral  stimulant  and  depressant, 

26 

constitution,  121,  131 
convulsant  action  of,  24 
distoxication  of,  127 
elective   action   on   sensory   fibres, 

123-124 

endermic  injection  of,  128 
eye,  action  and  uses  in  the,  158 
gastric  secretion,  action  of,  on,  167 
general      pharmacological      action, 

122  ff. 

history,  121,  122 
in  infiltration  anaesthesia,  128 
intra-ocular  tension,  effect  on,  158 
metabolism,  action  on,  382 


INDEX 


591 


COCAINE,  nerve  blocking  by,  123 

nerves  of  special  sense,  action  on,  123 

poisoning  by,  126 

treatment  of,  126 

principles  governing  administration, 
127 

pyrogenic  action  of,  462,  473 

respiration,  stimulating  action  on,  335 

sensory  nerve-endings,  action  on,  122 

special  senses,  action  on,  123 

spinal  anaesthesia  by,  129 

substitutes  for,  131  ff. 

comparative  value  of,  133  ff . 

swallowing  reflex,  action  on,  176 

synergism  between  epinephrin  and, 
159,575 

systemic  action,  125 

therapeutic  employment  of,  125 

toxicology,  126 

vessels,  action  on,  124 

in  vomiting,  185 
CODEINE  CHEMISTRY,  31 

cough,  in  treatment  of,  38 

morphine,  differences  from,  38 

respiratory  centre,  action  on,  340 
COD-LIVER  OIL,  174 
COLD,  antiphlogistic  action  of,  492 

heat-regulating   mechanism,    action 
on,  453-455 

vessels,  influence  on,  453,  454 
COLIC,  intestinal,  mechanism  of,  194 
COLLAPSE,  antipyretics  as  cause  of,  466 

atropine,  camphor,  and  cocaine  in, 
25 

mechanism  of,  309 
COLLOIDS,  obstipant  action  of,  211 

and  salts,  570 
COLOCYNTH,  192,  206 
CONCENTRATION  IN  BLOOD,  562 
CONDIMENTS,  stomach  absorption,  effect 
on,  173 

secretion,  action  of,  on,  167 
CONSTIPATION,  drugs  causing  (see  Ob- 
stipants) 

CONVALLAMARIN,  302 
CONVTTLSANTS,  23 

temperature,  action  on,  462,  473 
COPAIBA,  367,  486 
COPPER,  elimination  in  bile,  170 

by  intestine,  172 
muscular  paralysis  from,  427 
salts,  in  inflammation,  494 
sulphate,  emetic  action  of,  182 

phosphorus,  antidotef  or,  183, 408 
toxicity,  lack  of,  182 
CORIAMYRTIN,  action  on  central  nervous 

system,  24 
CORNUTINE,  226 
CORROSIVES,  eye  action  in,  160.     (See 

also  Caustics) 

CORONARY  (see  under  Circulation,  ves- 
sels, coronary) 

COTARNINE,  uterus  action  on,  229 
GOTO,  diarrhoea  in,  215 


COUGH,  morphine  group  in,  339,  340 

COUNTERIRRITANTS,  486  ff . 

leucocytes,  action  on,  447 

respiration,  action  on,  341 
COUNTERIRRITATION,   explanation  of  ef- 
fects, 484 
CREOLIN,  517 
CREOSOTE  COMPOUNDS,  526 

in  tuberculosis,  525-527 
CRESOLS,  action  on  liver,  517 

as  disinfectants,  516,  517 

relative  toxicity  of,  517 
CROTON  OIL  (see  Oleum  crotonis) 
CUBEBS,  367,  486 
CUMULATION,  563 
CURARE,  1  ff . 

absorption,  5 

antagonism  between  physostigmine 
and,  9,  152,  572 

central  nervous  system,  action  on,  4 

circulation,  action  on,  4 

excretion,  5 

frog,  action  on,  2 

glycosuria,  5 

heart,  action  on,  247 

immunity  of  salamanders  to,  573 

intestine,  action  on,  4 

mammals,  action  in,  4 

motor  nerve-endings,  action  on,  1 

in  strychnine  poisoning,  19 

rigor  of  muscles,  influence  on,  424 

substances  resembling,  8 

therapeutic  use,  7 
CURARINES,  2 

CURINE,  2 

CYANIDE  POISONING,  450,  569 

distoxication  of,  569 
CYTOTOXINS,  560 

DEGLUTITION,  as  affected  by  drugs,  176 
DERMATOL,  216 

DIABETES  INSIPIDUS,     drugs     used     in 
treatment,  366 

mellitus,  418 

DIABETIC  COMA,  alkalies  in,  392 
DIAPHORESIS,  371-375 

indications  for,  375 

in  renal  disease,  375 
DIAPHORETICS,  central,  372,  373 

peripheral,  372 
DIARRHCBA,  drugs  checking  (see  Obsti- 

pants) 
DIETHYL  BARBITURIC  ACID  (see  Veronal) 

DlGALEN,  301,  306 
DlGIPURATUM,  306 
DlGITALEIN,  301 
DlGITALIN,  301,  304 

DIGITALIS,  active  principles,  301 

blood-pressure  increase  from,  292 
bodies,  differences  in  actions  of,  302 
relative  cumulative  properties 

of  different,  303,  304 
vaso-constricting  power,  differ- 
ences in  their,  288 


592 


INDEX 


DIGITALIS,  cardiac  failure,  action  in,  310 
circulatory  collapse,  effects  in,  323 
cumulative  effects,  303 
deterioration  of,  302 
distribution  of  the  blood,  effects  on, 

296 

diuretic  action  of,  365  ff. 
dosage  and  choice  of  preparation, 

304, 305 

extra-systoles,  power  of  causing,  267 
heart,  action  on,  261-267 

conductivity,   action    on,   266, 

267 

disease,  effects  in,  296  ff. 
frog's,  action  on,  262-264 
isolated  mammalian,  action  on, 

264,  265 

toxic  doses,  effect  on,  266 
work,  effect  on,  293,  294 
infusions,    rapid    deterioration    of, 

302,  305 
intestinal  motor  function,  action  on, 

188,  191 

intravenous  administration,  306 
kidney  vessels,  effect  on,  287,  299 
physiological  assay,  methods,  301 
practical  employment  of,  301  ff. 
preparations,  variability  of,  301 
pulse  retardation,  292 
pulse  volume  of  heart,  effect  on,  293 
regulatory  action  of,  266,  294 
retardation  of  pulse  by,  292 
stomach  and  intestinal  movements, 

action  on,  188 
summary  of  actions,  300 
theory  of  action  of,  291 
toxic  action  of,  294 
vagus,  action  on,  245,  266,  292 
vasoconstriction  under  clinical  con- 
ditions, 298  ff . 

vessels,  renal,  action  on,  287,  299 
of   different   organs,    quantita- 
tively   different    action    on, 
286,287 

peripheral  action  on,  286-288 
vomiting  due  to,  304,  306 
DIGITONINS,  301 
DIGITOXIN,  301 

importance  of  size  of  dose,  564 
DIMETHYLXANTHINES,  action  in  kidney, 

289 
DIONIN,  38 

in  cough,  340 
eye,  action  in,  161 
respiration,  action  on,  340 

DlOXYDIAMIDOARSENOBENZOL     (see    Sal- 

varsan) 

DIPHTHERIA,  553  ff. 
antitoxin,  556-558 
toxin,  555,  556 

action  on  vessels,  483 
on  heart,  309 

DlPROPYLBARBITURIC     ACID    (see   Propo- 

nal) 


DIRECT  ACTION,  6 

DISINFECTANTS  (see  also  Antiseptics) 

specific,  523  ff . 

in  vitro  and  in  corpore,  525 
DISINFECTION  of  instruments,  etc.,  508 

mucous  membranes,  508,  509 

skin,  507 

wounds,  508,  509 
DISTOXICATION,  569 

augmentation  of  power  of,  574 
DISTRIBUTION,  562 

factors  affecting,  562 
DIURESIS,  ascites,  effect  of  relief  of,  357 

blood  flow  in  kidney  as  factor  in. 
357  ff. 

blood  letting,  effect  on,  354 

caffeine  group,  action  on,  360 

cardiac  stasis,  effect  on,  357 

digitalis  group,  action  on,  365 

factors  controlling,  354 

hydraemia,  effect  on,  354 

reflex  inhibition  of,  358 

saline  infusions,  effect  on,  354 

sugars,  action  on,  356 

tubules,  function  of,  factors   influ- 
encing, 366 

vasoconstriction,    renal,    effect    on, 
358 

urea  as  stimulant  to,  356 

vasodilatation,  renal,  effect  on,  359 
DORMIOL,  93 
DRASTIC  PURGATIVES,  207 

abortifacient  action  of,  223,  224 
DUBOISINE,  pancreatic  secretion,  action 
of,  on,  168 

FCGONINE,  132,  133,  154 

ECHUYIN.  302 

EHRLICH  s  side-chain  theory,  550  ff . 

ELECTIVE  ACTION,  5 

ELIMINATION  of  drugs  in  milk,  220 
rapidity  of,  562 

EMESIS,  181-185 

drugs  sometimes  causing,  185 
treatment  of,  185 

EMETIC  CENTRE,  depressants  of,  178 

EMETICS,  centrally  acting,  179,  180 
expectorant  action  of,  179,  343 
peripheral,  181-185 

EMETINE,  181,  182 

EMODIN,  207 

ENEMATA,  194 

ENZYMES,  as  caustics,  492 

EPHEDRINE  and  pseudo-ephedrine,  159 

EPINEPHRIN,  279-285 

accelerator,   peripheral,    action  on, 

252 

analeptic  action  of,  321,  322 
anaesthesia,  local,  use  in,  280 
antiphlogistic  action  of,  496 
arteriosclerosis,  a  cause  of,  282 
asthma,  action  in,  346 
blood-pressure,  effects  on,  281 
in  chloroform  death,  65,  320 


INDEX 


593 


EPINEPHBIN,  circulatory  failure,  in  treat- 
ment of,  320  ff. 

coagulability  of  blood,  action  on,  448 
constitution,  279 
coronary  vessels,  action  on,  280 
diuresis,  action  on,  358 
elimination,  282 

evanescence  of  action,  cause  of,  282 
eye,  action  in,  159, 282 
fibrillation    of    heart,  a   cause    of, 

322 

glycosuria,  282,  419 
in  haemorrhage,  321 
haemostatic  action  of,  280 
heart,  action  on,  260,  261 
hi  heart  failure,  320,  321 
hepatic  function,  action  on,  171 
hypertension,  a  cause  of,  323  ff . 
intestinal  motor  function,  action  on, 

191 

intravenous  use  of,  321 
kidney,  action  on  vessels  of,  280 
and  pancreas  hormone,  568 
pulmonary  vessels,  action  on,  280 
pyrogenic  action  of,  462,  463 
reaction  in  pancreatic  disease,  159 
respiration,  action  on,  282 
salivary  glands,  effect  on,  164,  282 
seat  of  action,  282 
significance  (physiological),  for  the 

blood-pressure,  284 
in  shock,  321 
spinal  anaesthesia,  in  collapse  from, 

321 

stomach  movements^  action  on,  188 
subcutaneous  injections,  effects  of, 

322 

sweat  glands,  lack  of  action  on,  372 
and  the  sympathetic  nerve-endings, 

141 
synergism  between  cocaine  and,  159, 

160,  575 

tests  for,  physiological,  283 
uterine  movements,  action  on,  222, 

223,  229 

vagus  centre,  effect  on,  282 
vascular  depression,  in  treatment  of, 

320  ff. 

vasomotor  paradox,  226 
vessels,  action  on,  279-283 
vascular  paresis,   in  treatment  of, 

320  ff. 
EPSOM  SALT  (see  Magnesium  sulphate, 

also  Cathartics,  saline) 
ERECTION,  219 
ERGOT,  224-228 

active  principles  of,  225-227 

instability  of,  227 
cock's  comb,  action  on,  226 
hi  hemorrhage  from  uterus,  228 
physiological  assay  of,  227 
preparations  of,  228 
therapeutic  uses  of,  228 
vasoconstrictor  action  of,  228 


ERGOTIN,  stomach  and  intestinal  move- 
ments, action  on,  188 
ERGOTISM,  224,  225 
ERGOTOXIN,  225,  226,  227 

circulation,  action  on,  226 
sympathetic   nerve-endings,    action 

on,  142 

ERYTHROL  TETRANITRATE,  329 
ERYTHROPHLEIN,  302 
ESCHAROTICS,  491  ff. 
ESERINE  (see  Physostigmine) 
ETHER,  49-55 
ETHER  ANESTHESIA,  after  effects,  73,  74 

blood-pressure,  effects  on,  62 
asthma,  action  in,  345 
blood  cells,  action  on,  56 
chemistry  of,  53 
circulation,  action  on,  60  ff . 
circulatory  failure,  in  treatment  of, 

317 

concentration  in  air  inspired,  72,  73 
in  blood  during  anaesthesia,  70,71 
excretion,  55 
general  action,  54 

heart,  stimulating  action  on,  257, 258 
local  action,  54 

anaesthetic  action,  54,  56 
respiration,  action  on,  59,  335 
a  respiratory  stimulant,  335 
synergism,  79,  576 
vasomotor  centres,  action  on,  62 
vessels,  action  on,  275 
ETHEREAL  OILS,  abortifacient  action  of, 

224 

antiphlogistic  action  of,  496 
carminative  action,  211 
diuretic  action  of,  359 
gastric  secretion,  action  on,  167 
kidney  secretion,  action,  359 
ETHYL  RROMIDE  anaesthesia,  83 

chloride,  local  anaesthesia  by,  118 
ETIOTROPIC     pharmacological     agents, 

497  ff. 

EUCAINE,  133 
B,  133 

relative  toxicity  of,  134 
action  on  vessels,  135 
EUMYDRINE,  mydriatic  action,  157 
EUONYMIN,  206,  302 
EUPHTHALMINE,  mydriatic  action,  157 
EUQUININE,  476 
EUROPHEN,  520 

EXCITABILITY,  exaltation  of,  44 
EXPECTORANTS,  342  ff . 
mode  of  action,  342 
nauseant,  343 

effect  on  alveolar  air,  339 
EYE,  antiseptics  in,  160 
astringents  in,  160 
corrosives  in,  160 
pharmacology  of  the,  144  ff . 

FELIX  MAS,  521 

causing  toxic  amblyopia,  144 


594 


INDEX 


FENNEL,  carminative  action,  211 

FERBATIN,  442 

FEVER,  mechanism  of,  459-463 

puncture  hyperthermia,  460,  461 

significance  of,  473-475 

substances  causing,  462 
FIBROLYSIN,  489 
FILICIC  ACID,  522 
FILICIN,  522 
FORMALDEHYDE,  astringent  action,  493 

as  disinfectant,  507 
FRANGULA,  208 
FUNCTIONAL  CONDITION  of  organs,  566 

GALL-BLADDER,  atropine,  action  on,   169 

pilocarpine,  action  on,  169 
GAMBOGE,  206 
GASTRIC  HYPERSECRETION,  inhibition  of, 

167 

motility  (see  Stomach,  motor  func- 
tion of) 
secretion,  165-^167 

acids,  action  of,  on,  165 
albuminoses,  action  of,  on,   165 
alkalies,  action  of,  on,  165 
atropine,  action  of,  on,  166 
bismuth,  action  of,  on,  167 
bread,  action  of,  on,  165 
choline,  action  of,  on,  166 
cocaine,  action  of,  on,  167 
condiments,  action  of,  on,  167 
fats,  action  of,  on,  165 
lime  water,  action  of,  on,  167 
local  anaesthetics,  action  of,  on, 

167 

magnesia,  action  of,'  on,  167 
meat  extractives,  action  of,  on, 

165 

morphine,  action  of,  on,  166 
protect! ves,  action  of,  on,  167 
GELATINE,  coagulability  of  blood,  action 

on,  448 
GENITAL  GLANDS,  metabolism,  influence 

on,  398 
GLAUBER'S  SALT  (see  Sodium  sulphate, 

also  Cathartics,  saline) 
GLAUCOMA,  effect  of  atropine  in,  155 
of  cocaine  in,  158 
of  physostigmine  in,  150 
GLOTTIS,  drugs  acting  on  spasm  of,  345 
GLYCERINE,  intestine,  action  on,  194 
GLYCOSURIA,  asphyxial,  agents    causing, 

418 

drugs  causing,  418,  419 
phloridzin,  419 
renal,  drugs  causing,  419 
suprarenal,  419 

thyroid  substances  causing,  397 
GLYCOSURIAS,  toxic,  418 
GLYCURONIC  ACID,  420 
GOUT,  atophan  in,  421 

alkalies  in,  390,  391 
GUAIACOL,  526 

compounds,  526,  527 


ILEMOLYTIC  TOXINS,  452,  559 

HAEMOLYSIS,  451  ff.,  559 

as  measure  of  intensity  of  phanna> 

cological  action,  564 
HALOGEN  SALTS,  elimination    by    intes- 
tines, 172 
HASHISCH,  41 

HEADACHES,  antipyretics  in,  475 
HEART  (see  under  Circulation) 
HEAT,  heat-regulating  mechanism,  action 

on,  455,  456 
action  on  vessels,  290 
regulating  centres,  abnormal  func- 
tion in  fever,  459,  460,  461 
cooling  a  stimulant  to,  457 
depression  of,  458 
location  of,  458 

overheating  a  depressant  of,  458 
stimulation  of,  457 
regulation,   pharmacology  of,   453- 

480 

physiology  of,  453-458 
HEDONAL,  95 
HELLEBOREIN,  302 
HELMITOL,  367 

HEROIN,  respiration,  action  on,  38,  340 
HEXABROM  -  DIOXY  -  DIPHENYLCARBINOL, 

525 
HEXAMETHYLENAMINE,    elimination   by 

bile,  170 

salivary  glands,  165 
as  urinary  disinfectant,  367 
HIDROTICS  (see  Diaphoretics) 
HIPPOL,  367 
HIRUDIN,  448 
His,  bundle  of,  digitalis's  action  on,  266, 

267,  295 
HOMATROPINE,  mydriatic  action,  157 

HOMCEOPATHY,  561 

HYDR^MIA,  effect  on  diuresis,  354 

produced  by  salts,  354,  355 
HYDRASTIN,  blood-vessels,  action  on,  229 

uterus,  action  on,  229 
HYDRASTININE,  blood-vessels,  action,  229 

uterus,  action  on,  229 
HYDRASTIS,  uterus,  action  on,  229 
HYDROCARBON  NARCOTICS,  43  ff.     (See 
also  Hypnotics  of  Alcohol  group  and 
Alcohol  group) 

HYDROGEN  PEROXIDE  as  disinfectant,  511 
HYDROGEN  SULPHIDE  (see  Sulphuretted 

hydrogen) 

HYOSCINE  (see  Scopolamine) 
HYOSCYAMJNE,  d-  and  b-,  154 
HYPER^EMIA,    passive,     explanation    of 

effects,  485 

HYPERSUSCEPTIBILITY,  577 
cellular,  to  toxins,  578 
due  to  peculiar  composition  of  body 

fluids,  578 

from  abnormal  tone  of  nerves,  577 
from  lime  poverty,  577 
HYPNOTICS,  absorption  and  elimination, 
importance  of  rate  of,  84 


INDEX 


595 


HYPNOTICS  of  alcohol  group,  84  ff. 
general  action,  84 
side  actions,  85 
of  aliphatic  series,  heart,  'depressant 

action  on,  252,  253 
chemical  constitution  and  pharma- 
cological action,  98  ff. 
depth  of  sleep,  effects  on,  86,  87 
halogen-free  compared  with  .halo- 
gen-containing, 93 
influence  of  halogen  groups  in,  99 
motor  function,  varying  action  on, 

of  different,  87 

HYPOPHYSIS  EXTRACTS,  uterine  contrac- 
tions, action  on,  223,  230 
metabolism,  influence  on,  398 
HYPOSULPHITES,  in  nitril  posioning,  569 
HYPOTHYROIDISM,  396 


ICHTHYOL,  518 

IDIOSYNCRASY,   578.     (See  also  Hyper- 
susceptibility,  578,  and  Anaphylaxis, 
580) 
IMMUNITY,  573 

active  and  passive,  544 
cellular,  573 
INDIRECT  ACTION,  6 
INFILTRATION  ANAESTHESIA,  120,  128 
INFLAMMATION,  excitation  of,  481-^492 
influence  of  caustics  on,  483,  484 
of    irritants    and    counterirri- 

tants  on,  482 
of  necrotizing  agents  on,  483, 

484 

of  nerves  on,  481,  482 
of  vascular  poisons  on,  483 
inhibition  of,    492-496.      (See  also 

Antiphlogistic  agents,  etc.) 
nature  of,  481 
pharmacology  of,  481-496 
INFUSIONS,  blood,  in  circulatory  failure, 

318 
effect  on  concentration  of  blood, 

437 
in  carbon  monoxide  poisoning, 

450 

saline,  blood   regeneration,  in- 
fluence on,  435 
blood  volume,  effect  on,  435 
circulatory    failure,    in    treat- 
ment of,  318 

haemorrhage,  value  in,  319 
toxaemias,  value  in,  319 
INHALATIONS,  action  on  lungs,  341 

antiseptic,  341 
INHIBITION,  removal  of,  44 
INSOMNIA,  causes,  85 
INSUSCEPTIBILITY,  573,  574 
to  cantharidin,  574 
to  emetics,  574 
of  morphinist  to  cocaine,  574 
of  mice  to  CO,  574 
of  young  animals  to  strychnine,  574 


INTERNAL  SECRETIONS,  metabolism,  in- 
fluence on,  398 
INTESTINAL  DISINFECTION,  201,  204,  520 

juice,  secretion  of,  171,  172 
INTESTINE,  absorption  in,  173 

large,  cathartics  acting  on,  207  ff. 

motor  function,  190  ff. 

small,  cathartics  acting  on,  205  ff . 

elimination  by,  172 
IODIDES  (see  also  Iodine) 

in  asthma,  347 

in  atheroma,  402 

elimination  by  saliva,  164 

expectorant  action  of,  343 

in  metallic  poisoning,  402 

in  neuralgia,  402 

in  syphilis,  401 

viscosity  of  blood  action  on,  448 
IODINE  (see  also  Iodides) 

compounds,  402 

as  counterirritant,  488 

ion  action  of,  399 

local  action,  398,  488 

metabolism,  action  on,  398-402 

mucous  membranes,  action  on,  400 

nutrition,  action  on,  400 

poisoning  from,  488 

scrofula,  action  in,  401 

skin,  action  on,  400 

systemic  actions,  399-402 

theory  of,  action  of,  400,  401 

thyroid  gland,  action  on,  400 
IODIPIN,  402 
IODOFORM,  518,  519 

toxicology,  519 

idiosyncrasy  to,  580 

substitutes  for,  519,  520 
IODOL,  520 

IODOTHYRIN,    395.      (See   also   Thyroid 
substances) 

hepatic  functions,  action  of,  on,  171 
IPECAC,  181,  182 

in  dysentery,  181,  182 

emetic  action  of,  181 

expectorant  action,  343 
IRIS,  pharmacology  of,  145-159 
IRON,  alimentary  canal,  behavior  in,  442 

blood,  actions  on,  435-443 

comparative  value  of  different  prep- 
arations of,  442 

content  of  foods,  441 

excretion  of,  172,  438 

in  food  stuffs,  441 

inorganic,  absorption  of,  439 
effect  on  iron  balance,  438 
preparations,  442 
relative  superiority,  440  ff . 

transformation  into  haemoglobin,  439 

kidney,  lack  of  action  on,  443 

metabolism,  action  on,  415 

non-toxic  by  mouth,  439 

organic  preparations,  442 
relative  inferiority,  440 

transformation  into  haemoglobin,  440 


596 


INDEX 


IRON  salts  in  inflammation,  494 
sulphate,  as  deodorant,  507 
tonic  effect,  441 
toxicology,  442,  443 

IRRITANTS,  phlogistic  effects  of,  482 

ISOFORM,  520 

TSOPRAL,  93 

ISOVALERYLUREA,   halogen   compounds, 
100 

ITROL,  513 

JABORANDI,  373 
JALAP,  206 

JAMBUL  in  diabetes,  418 
JUNIPER,  oil  of,  486 

JUNIPERUS  SABINUS,  abortifacient  action 
of,  224 

KAIRINE,  477 

KALAHARI  arrow  poison,  483 

KAMALA,  523 

KIDNEY,  blood  flow  in,  estimation  of,  358 

vessels,  digitalis  action  on,  365 
KINO,  214 
Koosso,  522 
Kousso,  522 
KOUSSOTOXIN,  522 
KRAMERIA,  214 

LACTAGOGUES,  220 

LEAD  ACETATE,  absorbability  of,  216 

astringent  action  of,  216 
elimination  in  bile,  170 
by  intestine,  172 
in  saliva,  165 

muscular  paralysis  from,  427 
organic  compounds,  toxicity  of,  533 
salts,  in  inflammation,  494 
vascular  crises,  a  cause  of,  325 
LECITHIN,  metabolism,  effect  on,  417 
LEUCOCYTES,  drugs  influencing,  446, 447 
LIME  (see  also  Calcium) 

coagulability  of  blood,  action  on,  447 

as  disinfectant,  506 

water,  alimentary  canal,  action  in, 

217 
gastric  secretion,  action  of,  on, 

167 

LIVER,  functions  of,  and  epinephrin,  171 
and  iodothyrin,  171 
and  pancreatic  internal  secre- 
tion, 171 

LOBELINE,  asthma,  action  in,  345 
emetic  action,  180 
respiration,  stimulating  action  on, 

335 

LOCAL  ANESTHETICS,  gastric  secretion, 
action  of,  on,  167.     (See  also  under 
Cocaine) 
LORETIN,  520 
LOSOPHAN,  520 
LYSIDIN,  421 
LYSOL,  517 


MAGNESIA,  antidote  for  arsenic,  202 
calcined,  202 

gastric  secretion,  action  of,  on,  167 
usta  (see  Magnesia) 
MAGNESIUM,  anaesthetic  action  of,  110 
central  nervous  system,  action  on, 

110 

toxic  action,  202 
sulphate,  201 
MAMMARY  GLAND,  influenced  by  other 

organs,  220 
secretion,   elimination  of  drugs  in, 

220 

MANGANESE,  blood,  action  on,  443 
MANNITE,  203 

MASSAGE,  metabolism,  effect  on,  379 
MEAT    EXTRACTIVES,   gastric    secretion, 

action  of,  on,  165 
MENTHOL,  elimination  in  bile,  170 
MERCURIC  SALTS,   antiseptic  power  in- 
fluenced by  dissociability  of, 
501-503 
differences  in  antiseptic  powers, 

501-503 
MERCURIAL     amalgam     in     inhalation 

curves,  541 
MERCURY,   bichloride   of,    as  injection, 

541,  542 

intravenous  injections,  542 
blood,  action  on,  415 
diuretic  action  of,  356 
double  salts  of,  502,  503 
elimination  in  bile,  170 
curves,  540-542 
by  intestine,  172 
in  saliva,  165 
inhalations,  541 
injections,  insoluble,  542 

soluble,  541,  542 
intestine,  toxic  action  on,  513 
inunctions,  541,  542 
kidney,  action  on,  542 
metabolism,  action  on,  415 
organic   compounds   for  injections, 

542 

organic  compounds,  toxicity  of,  533 
poisoning,  acute,  415,  416,  513 
chronic,  415,  416 
subacute,  513 
oral  administration,  541 
salicylate  of,  as  injection,  542 
salts,  as  disinfectants,  512 
in  syphilis,  539-543 
thymol-actetate  of,  as  injection,[542 
yellow  iodide  in  syphilis,  541 
METABOLISM,  alkalies,  action  on,  389 
arsenic,  action  on,  409 
carbohydrate,      pharmacology      of, 

418  ff. 

in  diabetes,  drugs  affecting,  418 
dehydration,  action  on,  387 
in  fever,  459,  460 

functional  activity,  influence  of,  381 
iodides,  influence  of,  398 


INDEX 


597 


METABOLISM,  light,  action  on,  382 
mineral,  418 

osmotic  changes,  action  on,  384,  385 
pharmacology  of,  377 
phosphorus,  405 
physiology  of,  377-381 
quinine,  influence  on,  403 
of  purines,  421 
special  phases  of,  417  ff. 
stimulation  of,  378-380 
temperature  of  body,  influence  on, 

382 

thyroid  substances,  influence  on,  395 

water  ingestion,  action  on,  384-386 

METALLIC  SALTS,  antiseptic  actions,  514, 

515 

astringent  action,  215  ff. 
as  caustics,  491 

METH.EMOGLOBIN,  drugs  causing  forma- 
tion of,  451 
METHYLATROPINE,  157 
METHYL  CHLORIDE,  local  anaesthesia  by, 

118 

ecgonine,  131 
METHYLENE  BLUE,  elimination  in  bile, 

170 

MIGRAINE,  nitrites  in,  329 
MIGRAININE,  479 

MILK  (see  Mammary  secretion,  220) 
MIOSIS  due  to  arecoline,  153 
choline,  153 
muscarine,  153 
nicotine,  153 
physostigmine,  148  ff. 
picrotoxine,  147 
pilocarpine,  153 
MIOTICS,  centrally  acting,  147 

peripheral,  147-153 
MODE  of  administration,  562 
MORPHINE,  as  analgesic,  36 

antagonism  to  atropine,  336 
antidotes  for,  36 
antipyretic  action,  465 
bladder,  action  of,  on,  34 
as  cerebral  stimulant,  33 
chemistry  of,  30,  31 
circulation,  action  of,  on,  34 
compared  with  ether  and  chloro- 
form, 58 

constipating  action  of,  193 
constitution,  30 
convulsive  action  of,  32 
cough,  effects  on,  37,  339 
deglutition,  effect  on,  176 
a  digitalis  of  the  respiration,  339 
elimination  by  intestine,  36,  40,  172 
by  saliva,  165 
by  kidney,  40 
by  stomach,  35 
emetic  action,  34,  180 
euphoric  action,  33 
fate  in  body,  40 
foetus,  action  on,  35,  575 
frog,  action  on,  31 


MORPHINE,  gastric  secretion,  action  of, 

on,  166 

habituation,  causation  of,  39,  574 
higher  animals,  action  of,  in,  32 
as  hypnotic,  37 
insusceptibility  acquired  by  cerebral 

cells,  574 
intestinal  motor  function,  action  on, 

192 

intestinal  secretion,  193 
lethal  dose,  34 
miotic  action,  34,  147 
motor  areas,  action  on,  32,  33 

reactions,  action  on,  33 
as  narcotic,  29 
pain,  action  on,  32 
pancreatic  secretion,  action  on,  168 
poisoning,  acute,  34 

acute,  treatment  of,  35 
pupil,  action  on,  34,  147 
respiratory  centre,  action  of,  on,  33, 

337  ff. 

and  scopolamine,  42,  79,  575 
scopolamine  anaesthesia,  79 
source  of,  30 

stomach  absorption,  effect  on,  173 
movements,  action  on,  188,  189 
secretion,  166,  189 
synergism    with    ether    or    nitrous 

oxide,  575 

tetanic  action  of,  31,  32 
therapeutic  uses,  36 
uterine  contractions,  action  on,  223 
variability   of   effects   in   different 

animals,  32 
vessels,  action  on,  276 
MORPHINISM,  39 

MOTOR  NERVE  ENDINGS,   1  ff. 

depression  of,  1  ff. 
stimulation  of,  9  ff . 
MUCILAGINOUS   SUBSTANCES,    obstipant 

action  of,  211 
MUSCARINE,    antagonism    to    atropine, 

249,  250,  569,  571 
autonomic  nervous  system,  action 

on,  142 

constitution,  248 
heart  action  on,  246-249 
miotic  action  of,  153 
poisoning,  251 

salivary  secretion,  action  on,  164 

sweat  glands,  action  on,  372,  373 

MUSCLES,  anatomy  and  physiology,  422- 

424 

depressant  drugs,  427 
involuntary   (see  Pharmacology  of 

Vegetative  System) 
ionic  actions  on,  422 
pharmacology  of,  422-434 
red,  function  of,  423 
stimulants  of,  428  ff . 
water   content,   influence  of,  422- 

423 
white,  function  of,  423 


598 


INDEX 


MUSHROOMS,  haemolysin  in,  452 

poisoning,  251 

MUSK,  heart,  action  on,  257 
MUSTARD,  oil  of,  488 
MYDRIATICS,  centrally  acting,  147 

peripherally  acting,  153  ff. 

NAPHTHALIN,  as  intestinal  antiseptic,  521 

in  skin  diseases,  518 
NARCOSIS  (see  also  Anaesthesia,  Hypnot- 
ics, etc.) 
theory  of,  100  ff . 

distribution  coefficients,  105, 106 

of  narcotics  in  organism,  103 

elective  absorption  by  nervous 

system,  102 
importance  of  lipoid  solubility, 

101 

other  types  and  causes  of  nar- 
cosis, 108 

side  actions  of  narcotics,  107 
NARCOTICS  of  alcohol  group,  in  vascular 

crises,  325,  326 
vasodilator    action,     peri- 
pheral, 288 

of    alcohol-chloroform    group    (see 
Narcotics  of  Alcohol  group,  and 
Narcotics  of  Aliphatic  series) 
metabolism,  influence  on,  382 
respiratory  sedative  action  of,  337 
vessels,  action  on,  276 
NARCOTINE,  30,  37 
NERVE  BLOCKING,  117,  129 
NEURALGIAS,  antipyretic  group  in,  475 
NEURONAL,  97 
NICOTINE  (see  also  Tobacco) 

autonomic  nervous  system,   action 

on,  140  ff. 
central  actions,  373 
heart,  action  on,  246,  247 
intestinal  motor  function,  action  on, 

191 

miotic  action  of,  153 
stomach  movements,  action  on,  187 
sweat  glands,  action  on,  373 
uterine  movements,  action  on.  222, 

223 

NIGELLINE,  sweat  glands,  action  on,  372 
NIRVANIN,  132 

NITRILS,  distoxication  of,  569 
NITRITE  POISONING,  216,  451,  569 
from  saltpetre,  216 
from  bismuth  subnitrate,  216 
NITRITES  (see  also  Amyl  nitrite) 
in  angina  pectoris,  327-329 
asthma,  use  in,  346 
blood,  action  on,  451 
cerebral  vessels,  action  on,  329 
coronary  arteries,  dilating  action  on, 

327    " 

various,  differences  between,  329 
in  vasoconstriction,  327 
NITROUS  OXIDE,  anaesthesia,  80  ff. 

narcotic  action,  cause  of,  108 


NITROUS  OXIDE-OXYGEN  anaesthesia,  81 
NOSOPHEN,  520 
NOVOCAINE,  132 

relative  toxicity,  133, 134 

superiority  of,  134, 135 

OBSTIPANTS,  211  ff. 

mode  of  action,  211 

OILS,  ethereal,  action  on  gastric  secre- 
tion, 167 
on  kidney,  359 

OLEATES,  biliary  secretion,  action  on,  170 
OLEO-CROTONIC  ACID,  205 
OLEUM  CROTONIS,  cathartic  action  of,  203 
OLEUM  MORRHU.E,  174 
OLEUM  RICINI,  cathartic  action  of,  205 
OPIUM  (see  also  Morphine) 

alkaloids  other  than  morphine,  30,37 

composition  of,  30,  37 

diabetes  insipidus,  in  treatment  of, 
366 

in  diabetes  mellitus,  418 

eating,  41 

therapeutic  uses  of,  37 
ORTHOFORM,  132,  134 

new,  132 
OVARIAN  EXTRACT,  artificial  menopause, 

action  on,  218 
OVARIES,  choline,  action  on,  218 

uterus,  etc.,  influence  on  develop- 
ment of,  218 
OUABAIN,  302,  307 

OXALATES,  coagulability  of  blood,  action 
on,  448 

distoxication  by  calcium,  569 

intestine,  action  on,  175 
OXALURIA,  421 
OXIDATION,  substances  inhibiting,  404  ff. 

OXYANTHRAQUINONE   DERIVATIVES,    207 

OXYGEN  in  carbon  monoxide  poisoning, 

450 

inhalations,  332,  333 
lack  of,  effect  on  respiration,  333 
tension,  blood,  influence  on,  446 
metabolism,  influence  on,  404, 

405 
respiratory    centres,    influence 

on,  332 

OXYTOXICS,  221  ff.     (See  also  Uterine 
contractions,  drugs  influencing) 

PANCREAS,  internal  secretion  of,  169 

hepatic  function,  action  on,  171 

PANCREATIC  SECRETION,  168,  169 

atropine,  action  of,  on,  168 
choline,  action  of,  on,  168 
duboisine,  action  of,  on,  168 
morphine,  action  of,  on,  168 
pilocarpine,  action  of,  on,  168 

PANTOPON,  37 

PAPAIN,  as  caustic,  492 

PAPAVERINE,  30 

PARAFFIN  ENEMATA,  194 

PARAFUCHSIN,  536 


INDEX 


599 


PARAHYDROXYPHENYLETHYLAMINE,  226 
PARALDEHYDE,  87,  93 
PARAMIDOPHENOL,  478 
PARANEPHRIN  (see  Epinephrin) 
PARASYMPATHETIC  nervous  system  (see 

Autonomic  nervous  system) 
PARATHYROIDS,  396 
PELLETIERINE,  523 

toxic  amblyopia  from,  144 
PENETRATING  POWER,  561 
PENTAMETHYLENEDIAMINE  in  ergot,  225 
PERMANGANATE  OP  POTASH  (see  Potas- 
sium permanganate) 
PERONIN,  38,  161,  340 
eye  action  in,  161 
respiration,  action  on,  340 
PHARMACOLOGICAL  ACTION,  factors  and 

principles  governing,  5 
nature  of,  6 

reactions,  factors  affecting,  561  ff. 
PHENACETIN  (see  Acetphenetidin) 
PHENOL,  antipyretic  action  of,  462,  473 
antiseptic  actions,  514,  515 
gangrene  from  local  application  of, 

119 

glycuronic  acid  and,  420 
kidney,  action  on,  516 
local  action,  515 

anaesthetic  action  of,  119 
poisoning,  515 

treatment  of,  516 
urine,  action  on,  516 
PHENOLPTHALEIN,  208 
PHENOLTETRACHLORPHTHALEIN,  209 
PHENYL  SALICYLATE  (see  Salol) 
PHLOGOGENIC  AGENTS,  483  ff. 
classification  of,  484 
PHLORIDZIN  GLYCOSURIA,  366,  419 
PHOSPHORUS,  blood,  action  on,  406 
bone,  action  on,  406,  407 
metabolism,  action  on,  405-408 
poisoning,  treatment  of,  408 
therapeutic  uses  of,  408 
toxicology,  407 
PHYSOSTIGMINE  ACCOMMODATION,  action 

on,  149 
antagonism  between  atropine  and, 

152,  572 

curare  and,  9,  152,  572 
autonomic  nerve  endings,  150  ff. 

nervous  system,  142 
central  actions,  152,  373 
glaucoma,  action  in,  150 
heart,  action  on,  152 

seat  of  action  in,  251 
intestinal  motor  function,  action  on, 

190 

intra-ocular  tension,  action  on,  149 
miotic  action,  148  ff. 
motor  nerve-endings,  9 
mucous  glands,  action  on,  151 
muscles,  action  on,  9,  151 
respiration,  action  on,  152 
salivary  secretion,  action  on,  151, 164 


PHYSOSTIGMINE,    stomach    movements, 

action  on,  187 

sweat  secretion,  action  on,  372,  373 
uterine  movements,  action  on,  222 
PHYTOTOXINS,  547 
PICROTOXIN,  antipyretic  action  of.  462, 

473 
autonomic  nervous  centres,  action 

on,  142 

convulsant  action  of,  23 
diaphoretic  action,  372 
medulla,  action  on,  24 
vasoconstrictor  and  vagus  centres, 

action  on,  274 

PILOCARPINE,  absorbant  effects  of,  375 
antagonism    to    atropine   in   sweat 

glands,  373,  572 
biliary  secretion,  action  on,  169 
bronchial  glands,  action  on,  343 
central  nervous  system,  action  on, 

374 

collapse  from,  374,  375 
diaphoretic  actions,  373 
eye,  action  on,  153 
general  actions,  374 
heart,  action  on,  247 
intestinal  motor  function,  action  on, 

190 

leucocytes,  influence  on,  447 
mammary  secretion,  action  on,  220 
metabolism,  action  on,  374 
pancreatic  secretion,  action  of,  on, 

168 

salivary  secretion,  action  on.  163 
stomach  motor  function,  action  on, 

187 

stomach  secretion,  action  on,  166 
secretions,  action  on,  373,  374 
uterine  movements,  action  on,  222, 

223 

PlPERAZINE,  421 

PIPERIDIN,  "curare"  action  of,  8 
PITUITRIN  (see  Hypophysis  extracts) 
Pix  LIQUID  A,  in  skin  diseases,  518 
PLACENTAL  EXTRACTS,  lactagogue  action, 

220 

PLUMBI  ACETAS  (see  Lead  acetate) 
PODOPHYLLIN,  206 
POLYCYTILEMIA,  446 
POTASSIUM  BITARTRATE,  202 
chlorate,  as  antiseptic,  511 
systemic  effects,  512 
toxicology,  512 

heart,  depressant  action  on,  253 
iodide  (see  also  Iodides  and  Iodine) 
mammary  secretion,  inhibitory 

action  on,  220 

permanganate  in  morphine  poison- 
ing, 36 

in  phosphorus  poisoning,  408 
as   disinfectant   and   preserva- 
tive, 511 

salts,  central  nervous  system,  action 
on,  111 


600 


INDEX 


POTASSIUM  SALTS,  diuretic  action,  356, 
359 

and  sodium  tartrate,  202 
PRECIPITINS,  560 
PRIMARY  ACTION,  6 
PRIMULA  TOXIN,  483 
PROPONAL,  97 
PROTARGOL,  514 

PROTECTIVES,   antiphlogistic  effects  of, 
493 

gastric  secretion,  action  on,  167 
PYRAMIDON,  480 
PYRAZOLON  DERIVATIVES,  479 
PYROGALLOL,  as  antiseptic,  517 

blood,  action  on,  451 
PYROGENIC  SUBSTANCES,  462 

collapse  action  of,  466 


QUEBRACHO  BARK,  180 

QUERCUS  ALBA,  214 

QUILLAJA  BARK,  expectorant  action,  344 

QUININE  AMBLYOPIA,  144 

antiphlogistic  action,  496 

antipyretic  action  of,  470,  471 

as  bitter,  476 

constitution,  476 

elimination  in  saliva,  165 

enzymes,  inhibitory  action  on,  403, 
471 

fate  and  excretion,  477 

fever,  action  in,  404 

heart,  depressant  action  of,  253 

heat-regulating  centres,  action  on, 
471 

leucocytes,  action  on,  447 

in  malaria,  527-529 

metabolism,  action  on,  403,  404 
of  proteid,  action  on,  403,  471 

muscles,  action  on,  403 

puncture  hyperthermia,  action  in, 
471 

salts  of,  476 

source,  475 

temperature,  action  on,  470,  471 

therapeutic  uses,  476 

tonic'action,  476 

toxic  action,  477 

in  typhoid,  471 

uterine'contractipns,  action  on,  223 
QUINOLINE,  constitution,  477 


RABIES,  vaccination  against,  544,  545 
RADIANT  ENERGY,  metabolism,  action  on. 

383 

RADIO-ACTIVE  WATERS,  383 
RADIUM,  metabolism,  action  on,  383 
RECTUM,  absorption  in,  174 

of  poisons  by,  174 
REMOTE  ACTION,  6 
RENAL  ANTISEPTICS,  364 

function  (see  also  Diuresis  and  Renal 
secretion) 


RENAL    FUNCTION,     pharmacology    of, 

348  ff. 

physiology  of,  348-354 
secretion,  blood  flow,  influence  on, 

350 

glomeruli,  role  played  by,  350 
impaired  permeability  of  glom- 
eruli, influence  on,  351 
sodium   chloride   group,    influ- 
ence on,  350 
theory  of,  349  ff. 
tubules,  role  played  in,  351,  352 
vasodilators,  360  ff. 
REPRODUCTIVE   ORGANS,    pharmacology 

of,  218 

RESINOUS  ACIDS,  cathartic,  206 
RESORCIN,  as  antiseptic,  517 
RESPIRATION,  counter-irritants,  action  on. 

341 

pharmacology  of,  332 
sedatives  (central)  of,  337-340 
stimulants  (central)  of,  334  ff. 
RESPIRATORY   CENTRES,   reflex  stimula- 
tion of,  336 

RETINA,  pharmacology  of  the,  144, 145 
action  of  carbonic  acid  on,  144 
of  chloroform  on,  144 
strychnine  on,  145 
santonin  on,  145 

augmentors  of  excitability  of,  145 
hypersesthesia  of,    drugs   relieving, 

144 

RHAMNUS  PURSHIANA  (see  Cascara) 
RHATANY,  214 
RHEUM  (see  Rhubarb) 
RHUBARB,  208 

RHUS  TOXICODENDRON,  phlogogenic  ac- 
tion, 483 

RINGER'S  SOLUTION,  388 
RONTGEN  RAYS  (see  X-rays) 
ROTTLERIN,  523 
RUBEFACIENTS,  482,  483 


SABROMIN,  115 
SACRAL  ANAESTHESIA,  120 
SAJODIN,  402 

SALICYLATES,  antipyretic  action  of,  472 
bile,  action  on,  170 
blood,  action  on,  451 
carbon  dioxide's  influence  on,  530 
in  diabetes,  366,  418 
diaphoretic  action,  374 
kidney,  action  on,  531 
leucocytes,  action  on,  447 
metabolism  of  proteid,  action  on, 

472 
uric    acid   metabolism,   action   on, 

421 

SALICYLIC  ACID,  antiseptic  action,  518 
group  of  antipyretics,  480 
as  intestinal  antiseptic,  521 
in  rheumatism,  529-531 
uterus,  action  on,  224 


INDEX 


601 


SALICYLISM,  480,  530,  531 

SALINE  INFUSIONS  (see  Infusions,  saline) 

SALIPYRINE,  479 

SALIVARY  GLANDS,  elimination  by,  165- 

(See  also  Salivary  secretion) 
secretion,  pharmacology  of,  162-165 
acids,  action  on,  163 
atropine,  action  on,  164 
bitters,  action  on,  163 
choline,  action  on,  164 
direct  stimulation  of,  163 
inhibition  of,  164 
mercury,  action  on,  164 
muscarine,  action  on,  164 
physostigmine,  action  on,  164 
pilocarpine,  action  on,  164 
reflex  stimulation  of,  163 
tobacco,  action  on,  164 
SALOL,  as  intestinal  antiseptic,  521 

renal  antiseptic  action,  367 
SALT-POOR  DIET,  diuretic  action  of,  356 
SALTS,  acid,  local  action,  394 
diuretic  action  of,  355 
as  diuretics,  contraindications  for, 

356 
neutral  (see  also  Sodium   chloride 

group) 

alkali  loss  produced  by,  388 
metabolism,  action  on,  387 

of  proteid,  action  on,  387, 

388 

skin,  action  on,  487 
stomach,  effect  on  movements 

of,  187 

SALVARSAN,  537  ff . 
constitution,  536 
employment  in  man,  537,  538 
elimination,  538 
in  relapsing  fever,  537 
in  syphilis,  538 
SANDALWOOD,  367,  486 
SANTONIN,  antipyretic,  action  of,  462, 473 
as  anthelmintic,  523 
convulsant  action  of,  24 
toxicology,  523,  524 
SAPONIN,  haemolysis  by,  452 

pharmacological  actions,  344 
SAPROL,  517 
SCAMMONY,  206 
SCILLAIN,  302 
SCLERERYTHRIN,  225 
L-SCOPOLAMINE,  154 
SCOPOLAMINE,  chemistry  of,  27 
eye,  action  in,  157 
as  a  hypnotic,  27,  28 
identity  with  hyoscine,  27 
motor  centres,  action  of,  on,  28 
mydriatic  action,  157 
relation  to  atropine,  27 
synergism,  with  morphine,  etc.,  42, 

79,  82,  575 
toxic  action,  28 

uterine  contractions,  action  on,  223 
variability  of  preparations  of,  29 


SCURVY,  role  of  neutral  salts  in,  388 

SEA  BATHS,  metabolism,  effect  on,  379 

SEA-SICKNESS,  chloral,  etc.,  in,  326 

SECALIN  TOXIN,  226 

SECONDARY  ACTION,  6 

SEIGNETTE  SALT,  202 

SENEGA,  expectorant  action,  344 

SENNA,  207 

SENSORY  NERVE-ENDINGS,  pharmacology 

of,  117 
nerves,  reflex  effects  of  stimulation 

of,  117 

SEPSIN,  capillary  dilating  action  of,  289 
SEQUARDINE,  434 
SERA,  bactericidal,  558 
SERUM  THERAPY,  546  ff . 
SIDE-CHAIN  THEORY,  550 
SILVER  NITRATE,  absorption  of,  216 

astringent  action  in  alimentary 

canal,  216 

in  inflammation,  494 
organic  compounds,  514 
salts  as  antiseptics,  513,  514 
chemotactic  power,  513 
SINIGRIN,  488 
SMELLING  SALTS,  336 
SNAKE  VENOM,  phlogogenic  action,  483 

sera  against,  551 
SODA  (see  Sodium  bicarbonate) 
SODIUM  BICARBONATE,  biliary  secretion, 

action  on,  170 

gastric  motility,  action  on,  186 
chloride,  diuresis,  action  on,  355, 356 
fever,  463 

group  as  expectorants,  343 
and  vegetable  diet,  449.     (See 

also  Salts,  neutral) 
ions,  action  on  muscles,  422 
nitrate,  nitrite  action  of,  330 
phosphate,  202 
salicylate,  therapeutic  effects,   480. 

(See  also  Salicylic  acid) 
sulphate,  201 

coagulability  of  blood,   action 

on,  448 

SOZOIODOL,  520 
SOZOIODOLIC  ACID,  516 
SPANISH  PLY  (see  Cantharidin) 
SPHACELIC  ACID,  226 
SPHACELOTOXIN,  226 
SPHYGMOGRAMS,  235 
SPINAL  ANALGESIA,  by  cocaine,  etc.,  129 

by  magnesium  salts,  110 
STASIS,  cardiac,  233 
STIMULATION,  significance  of,  43,  44 
STOMACH,  absorption  in,  172 

alcohol,  effect  on,  173 
bitters,  effect  on,  173 
carbonic  acid,  effect  on,  173 
condiments,  effect  on,  173 
colloids,  effect  on,  173 
motor  function  of,  186-189 

autonomic    drugs,    action 
on,  187 


602 


INDEX 


STOMACH,  secretory  function  of  (see  Gas- 
tric secretion) 
STOVAINE,  133,  134,  135 
STROPHANTHIN,  302,  304,  306,  307,  310 

in  circulatory  collapse,  323 

intravenous  use,  306,  323 
STROPHANTHUS  (see  Strophanthin) 
STRYCHNINE,  antidotal  action  of,  20 

brain  and  medulla,  action  of,  on, 
17 

chemistry  of,  13 

circulation,  action  of,  on,  18 

"curare,"  action  of,  19 

death,  cause  of,  19 

in  diabetes  insipidus,  366 

diaphoretic  action,  372 

diuresis,  action  on,  358,  366 

excretion  of,  21 

frog,  action  in,  13 

heart,  action  on  tone  of,  311 

higher  animals,  action  on,  16 

intestinal  motor  function,  action  on, 
191 

kidney  vessels,  action  on,  273 

metabolism,  action  on,  379 

muscular  function,   effect  on,  424, 
427 

paralytic  action  of,  18 

poisoning,  treatment  of,  19 

respiration,  action  on,  18 

a  respiratory  stimulant,  335 

retina,  action  on,  145 

seat  of  action  of,  14 

source  of,  12 

special  senses,  action  on,  18 

stomach  tone,  action  on,  188 

test  for,  13 

theory  of  action  of,  15 

therapeutic  uses,  20 

toxicology,  19 

vascular  depression,  in  treatment  of, 
311 

vagus  centre,  action  on,  245 

vasomotor  centres,  action  of,  on,  18, 

273 

STYPTICIN,  229 
STYPTOL,  229 
SUBLAMINE,  513 
Succus  ENTERICUS  (see  Intestinal  juice, 

171) 

SUDORIFIC  (see  Diaphoresis) 
SUGAR,  in  muscular  fatigue,  431 
SULPHATES,  in  lead  poisoning,  201 

in  phenol  poisoning,  201,  516 
SULPHIDES,  alkaline,  cathartic  action  of, 

209 

skin,  action  on,  487 
SULPHITES,  as  preservatives,  510 
SULPHO-CARBOLATES,  516 
SULPHONAL,  95,  96,  98 

blood,  action  on,  451 

group,  94  ff. 

SULPHONETHYLMETHANE   (see  Trfonal) 
SULPHONMETHANE    (see  Sulphonal) 


SULPHUR,  cathartic  action  of,  209 
skin,  action  on,  487 
toxic  action  of,  210 
SULPHURETTED  HYDROGEN,  210 

antidote  in  metallic  poisoning, 

210 
bronchial    mucous    membrane, 

action  on,  210 
local  action,  210 
SUPPURANTS,  489  ff. 
SUPRARENAL  (see  Epinephrin) 
SUPRARENALS,  metabolism,  role  in,  398 
SWEAT    (see    Diaphoresis    and    Antisu- 

dorifics) 

physiology  of,  369-371 
secretion  of,  369-376 

astringents,  action  on,  376 
inhibition  of,  375,  376 
SYMPATHETIC    NERVOUS    SYSTEM,    136- 

141 
anatomy    and    physiology 

of,  137, 138 

antagonism  between  auto- 
nomic    nervous    system 
and,  140 
SYNERGISM,  575 

of  antiseptics,  576 

between  cocaine  and  epinephrin,  159, 

575 

ether  and  chloroform,  79,  576 
magnesium  sulphate  and  chlo- 
roform, 575 
morphine,     scopolamine,     and 

ether,  79 
morphine  and  scopolamine,  79, 

82,  575 

of  opium  alkaloids,  576 
of  trypanosome  remedies,  576 
SYNERGISTIC   ACTIONS   on  temperature, 

473 

SYPHILIS,  iodides  in,  401 
mercury  in,  539-543 
SYSTEMIC  ACTION,  5 


TAMARIND,  203 
TANNALBIN,  215 
TANNIC  ACID  (see  Tannin) 
TANNIGEN,  215 
TANNIN,  214 

absorption,  214 

action  after,  214 
alimentary  canal,  action  in,  214 
compounds  of,  214 
dysentery  action  in,  182,  214 
TANNINS,  213 
TANNOCOLL,  215 

TANSY,  abortifacient  action  of,  224 
TARTAR  EMETIC  (see  Antimony  and  Po- 
tassium tartrate  and  antimony) 
TEMPERATURE     OP    BODY     respiration, 

action  on,  333 

drugs  affecting,  influence  on  metab- 
olism, 382 


INDEX 


603 


TESTICLES,  influence  on  secondary  sexual 

characteristics,  219 

TESTICULAR   EXTRACTS,   muscles,   influ- 
ence on,  433 
TETANUS,  552  ff. 
antitoxin,  554 
drugs  causing,  13 
incubation  period,  553 
toxin,  mode  of  distribution,  553 
TETRABROM-O-KRESOL,  525 
TETRAETHYL-AMMONIUM,  8 
B-TETRAHYDRONAPHTHYLAMINE,  159 
TETRAHYDRONAPHTHYLAMINE,  pyrogenic 

action  of,  462 

TETRAMETHYLENEDIAMINE  in  ergot,  225 
TETRAMETHYLAMMONIUM  IODIDE,  8 
TETRONAL,  95,  98 
THALLIN,  477 
THEBAINE,  304 
THEINE  (see  Caffeine,  314) 
THEOBROMINE  (see  also  Caffeine  and  C. 

group) 
accelerator,   peripheral,    action  on, 

252 

in  angina  pectoris,  330 
constitution,  360 
digestive  system,  action  on,  364 
diuretic  action  of,  364 
preparations  of,  364 
in  vascular  crises,  331 
vessels,  action  on,  274,  289,  330 
dilator  action  on  cerebral,  cor- 
onary and  renal.  289 
THEOCIN  (see  Theophylline) 
THEOPHYLLINE,  constitution,  360 
digestive  system,  action  on,  364 
diuretic  action,  364 
vessels,  action  on,  274.     (See  also 

Caffeine  and  Theobromine) 
THIOSINAMINE,  489 
THRESHOLD  DOSE,  564 
THUJA  OCCIDENTALS,  abortifacient  ac- 
tion of,  224 

THYMOL,  as  antiseptic,  517 
anthelmintic,  524 
as  intestinal  antiseptic,  521 
poisoning  from,  524 
in  uncinariasis,  524 

THYROGLOBULIN,  395.     (See  also  Thy- 
roid substances) 
THYROID    SUBSTANCES,    estimation    in 

blood,  397 

glycosuria,  resulting  from,  397 
in  hypothyroidism,  396 
metabolism,  influence  on,  395- 

397 

in  obesity,  396, 397 
poisoning  from,  397 
THYROIODIN,  395.     (See  also  Thyroid 

substances) 

TOBACCO  (see  also  Nicotine) 
as  abortifacient,  223 
amblyopia,  144 
poisoning,  circulation  in,  247 


TOXINS,    nature    and    properties,    546, 
547 

passage  along  nerves,  545,  553,  556 

vessels,  action  on,  276 
TOXOIDS,  550 

TRANSFUSION  (see  Infusions) 
TRIPERRIN,  442 
TRIONAL,  95,  98 

TROPAIC  ACID,  constitution,  154 
TROPACOCAINE,  131,  134 

action  on  vessels,  135 
TROPINE,  constitution,  153 
TRYPAN  RED,  536 
TRYPAROSAN,  536 
TRYPSIN,  as  caustic,  492 
TUBERCULIN,   phlogogenic  action,  483, 
490 

treatment,  546 
TURPENTINE,  486 

action  in  lungs,  487 

in  phosphorus  poisoning,  408 


URETHAN,  94 

in  asthma,  345 
URACIL  in  ergot,  225 
UREA,  diuretic  action  of,  356,  359 

renal  secretion,  influence  on,  350 
URIC  ACID  SOLVENTS,  421 
URINARY  ANTISEPTICS,  367 
URINE,  alkalies,  action  on,  368 

secretion  of  (see  Renal  secretion) 
UROTROPINE  (see  Hexamethylenamine) 
UTERINE  MOVEMENTS,    atropine,    action 

on,  222 
drugs  influencing — centrally  or 

reflexly,  223,  224 
pharmacology  of,  221  ff. 
pilocarpine,  action  on,  222 
UTERUS,  gravid  and  non-gravid,  differ- 
ence in  pharmacological  reactions,  222 
UVA  URSI,  367 


VAGUS  (see  Circulation,  Heart,  Inhibi- 
tory nerve) 
VALERIAN,   action  on   central  nervous 

system,  115 

in  diabetes  insipidus,  366 
VALIDOL,  115 
VALVYL,  115 

VASCULAR  (see  under  Circulation) 
VASOMOTOR,   etc.    (see   under   Circula- 
tion) 

VASOTONIN,  331 
VEGETATIVE  NERVOUS  SYSTEM,  136  ff. 

anatomy  and  physiology, 

136-138 

action  of  nicotine  on,  140 
VERATRINE,  antipyretic  effects,  426,  466 
blood-pressure,  action  on,  427 
cardiac  muscle,  action  on,  426 
circulation,  action  on,  427 
emetic,  action  on,  180 


604 


INDEX 


VERATRINE,  local  action,  427 
muscles,  action  on,  425-427 
nerves,  passage  along,  425 

VERATRUM  (see  Veratrine) 

VERONAL,  97 

VESICANTS,  489  ff. 

VESSELS  (see  under  Circulation) 


WATER,  absorption  of,  386 
diuretic  action  of,  354 
lack  of,  metabolic  effects,  387 
local  action,  385,  386 
metabolism,  action  on,  386,  387 
pharmacological  actions  of,  385-387 


XEROFORM,  520 

X-RAYS,  leucocytes,  action  on,  447 

metabolism,  action  on,  383 

ovaries,  effect  on,  218 

testicles,  effect  on,  218 

YEW  TREE  (see  Thuja  occidentalis) 
YOHIMBIN,  aphrodisiac  action,  219 

vessels,  elective  action  on  certain, 
289 

in  vascular  diseases,  331 

ZINC  SALTS,  in  inflammation,  494 
ZINC  SULPHATE,  emetic  action  of,  183 


THIS  BOOK  IS  DUE  ON  THE  LAST  DATE 
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WILL  BE  ASSESSED  FOR  FAILURE  TO  RETURN 
THIS  BOOK  ON  THE  DATE  DUE.  THE  PENALTY 
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DAY  AND  TO  $1.OO  ON  THE  SEVENTH  DAY 
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BIOLOGY  LIBRARY 


j   9,  9  1941 


LD  21-10m-7,'39(402s) 


369481 


UNIVERSITY  OF  CALIFORNIA  LIBRARY 


